Vitronectin receptor antagonists, their preparation and use

ABSTRACT

The present invention relates to compounds of the formula I,  
     A-B-D-E-F-G  (I)  
     in which A, B, D, E, F and G have the meanings given in the patent claims, to their preparation and to their use as medicaments. The compounds of the invention are used as vitronectin receptor antagonists and as inhibitors of bone resorption.

[0001] The present invention relates to compounds of the formula I

A-B-D-E-F-G (I)

[0002] in which A, B, D, E, F and G have the meanings given below, theirphysiologically tolerated salts and pharmaceutical preparationscomprising these compounds, and to their preparation and use asvitronectin receptor antagonists for the treatment and prophylaxis ofdiseases which are based on the interaction between vitronectinreceptors and their ligands in cell-cell or cell-matrix-interactionprocesses, for example inflammations, cancer, tumor metastasis,cardiovascular disorders such as arteriosclerosis or restenosis,retinopathies and nephropathies, and diseases which are based on anundesirable degree of bone resorption, for example osteoporosis.

[0003] Human bones are subject to a continuous, dynamic process ofreconstruction involving bone resorption and bone synthesis. Theseprocesses are regulated by cell types which are specialized for thesepurposes. While bone synthesis is based on the deposition of bone matrixby osteoblasts, bone resorption is based on the degradation of bonematrix by osteoclasts. Most bone disorders are based on an imbalance inthe equilibrium between bone formation and bone resorption. Osteoporosisis characterized by a loss of bone matrix. Activated osteoclasts aremultinuclear cells which have a diameter of up to 400 μm and whichdemolish bone matrix. Activated osteoclasts become attached to thesurface of the bone matrix and secrete proteolytic enzymes and acidsinto the so-called sealing zone, i.e. the region between their cellmembrane and the bone matrix. The acid environment and the proteasesdegrade the bone.

[0004] Studies have shown that the attachment of osteoclasts to bone isregulated by integrin receptors on the surface of the osteoclast cells.

[0005] Integrins are a superfamily of receptors which includes, interalia, the fibrinogen receptor a_(IIb)β₃ on the blood platelets and thevitronectin receptor α_(V)β₃. The vitronectin receptor α_(V)β₃ is amembrane glycoprotein which is expressed on the surface of a number ofcells such as endothelial cells, cells of the smooth musculature of theblood vessels, osteoclasts and tumor cells. The vitronectin V receptorα_(V)β₃ which is expressed on the osteoclast membrane regulates theprocess of attachment to bone and bone resorption and consequentlycontributes to osteoporosis. In this connection, α_(V)β₃ binds to bonematrix proteins, such as osteopontin, bone sialoprotein andthrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).

[0006] As vitronectin receptor antagonists, the novel compounds of theformula I inhibit bone resorption by osteoclasts. Bone disorders forwhich the novel compounds can be employed are, in particular,osteoporosis, hypercalcaemia, osteopenia, e.g. caused by metastases,dental disorders, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, and Paget's disease. In addition, the compounds ofthe formula I may be employed for the alleviation, avoidance or therapyof bone disorders which are caused by glucocorticoid, steroid orcorticosteroid therapy or by a lack of sex hormone(s). All thesedisorders are characterized by a loss of bone, due to an imbalancebetween bone synthesis and bone degradation.

[0007] Horton and coworkers describe RGD peptides and ananti-vitronectin receptor antibody (23C6) which inhibit tooth breakdownby osteoclasts and the migration of osteoclasts (Horton et al.; Exp.Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato etal. report that echistatin, an RGD peptide from snake venom, is a potentinhibitor of bone resorption in a tissue culture and an inhibitor of theattachment of osteoclasts to the bone. Fischer et al. (Endocrinology,1993, 132, 1411) showed that echistatin also inhibits bone resorption invivo in the rat.

[0008] The vitronectin receptor α_(V)β₃ on human cells of the smoothblood vessel musculature, of the aorta stimulates the migration of thesecells into the neointima, thereby leading finally to arteriosclerosisand restenosis following angioplasty (Brown et al., Cardiovascular Res.1994, 28, 1815).

[0009] Brooks et al. (Cell 1994, 79,1157) show that antibodies againstα_(V)β₃ or a antagonists are able to shrink tumors by inducing theapoptosis of blood vessel cells during angiogenesis. Cheresh et al.(Science 1995, 270, 1500) describe anti-α_(V)β₃ antibodies or α_(V)β₃antagonists which inhibit bFGF-induced angiogenesis processes in the rateye, a property which could be therapeutically useful in the treatmentof retinopathies.

[0010] Patent application WO 94/12181 describes substituted aromatic ornonaromatic ring systems, and WO 94/08577 describes substitutedheterocycles, which are fibrinogen receptor antagonists and inhibitorsof platelet aggregation. EP-A0 528 586 and EP-A0 528 587 discloseaminoalkyl-substituted or heterocyclyl-substituted phenylalaninederivatives, and WO 95/32710 discloses aryl derivatives, which areinhibitors of bone resorption due to osteoclasts. WO 96100574 and WO96/26190 describe benzodiazepines which are vitronectin receptorantagonists and integrin receptor antagonists, respectively. WO 96/00730describes fibrinogen receptor antagonist templates, in particularbenzodiazepines which are linked to a nitrogen-carrying 5-membered ring,which are vitronectin receptor antagonists. German patent applications P19629816.4, P 19629817.2 and P 19610919.1 and also EP-A0 796 855describe substituted aromatic ring systems or 5-membered ringheterocycles which are vitronectin receptor antagonists.

[0011] The present invention relates to compounds of the formula I,

A-B-D-E-F-G  (I)

[0012] in which:

[0013] A is

[0014] is a 5-membered to 10-membered monocyclic or polycyclic, aromaticor nonaromatic ring system which can contain from 1 to 4 heteroatomsfrom the group N, O and S and can optionally be substituted, once ormore than once, by R¹², R¹³, R¹⁴ and R¹⁵;

[0015] B is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene,(C₃-C₈)— cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,—NR²—C(S)—NR²—O—C(O)—, —NR²—S(O)—, —NR²—S(O)₂—, —O—, —S— or —CR²═CR³—,which can in each case be substituted, once or twice, by (C₁-C₈)-alkyl,for example—methyl-phenyl-methyl-, ethyl-NR²—C(O)— etc.;

[0016] D is a direct linkage, (C₁-C₈)alkanediyl, (C₅-C₁₀)-arylene, —O—,—NR²—, —CO—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—,—C(O)O—, —S(O)—, —S(O)₂—, —S(O)₂—NR²—, —S(O)—NR²—, —NR²—S(O)—,—NR²—S(O)₂—, —S—, —CR²═CR³— or —C≡C— which can in each case besubstituted, once or twice, by (C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl,for example methyl-phenyl-CH═CH—, ethyl-O— etc., with it not beingpossible for D to be —CO—NR²—, —C(O)O— —S(O)—, —S(O)₂—, —S(O)—NR²— or—S(O)₂—NR²— when B is a direct linkage;

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[0380] WO 95/00472, Jan. 5, 1995, Brewster, A G., et al. or

[0381] b) is a template which is defined analogously to the templatesfrom the series of fibrinogen receptor antagonists and which is takenfrom the following patent applications:

[0382] Smithkline Beecham Corp.

[0383] WO 96/00574, Jan. 11, 1996, Cousins, R. D., et al.

[0384] Fujisawa Pharmaceutical Co.

[0385] WO 95/29907, Nov. 9, 1995, Kawai, Y., et al.

[0386] Eli Lilly

[0387] U.S. Pat. No. 5,488,058, Jan. 30, 1996, Palkowitz, AD., et al.

[0388] U.S. Pat. No. 5,484,798, Jan. 16, 1996, Bryant, H. U., et al.;

[0389] or also is one of those templates which can be derivedstructurally from the templates which are described in the above patentapplications, patent documents and publications;

[0390] F is defined like D;

[0391] G is

[0392] R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl,which is optionally substituted, once or more than once, by fluorine,(C₃-C₁₂)cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₅C₁₄)-aryl,(C₅-C₁₄)-aryl-(C₁-C₁₄)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

[0393] R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine,OH, (C₁-C₈)-alkyl, (C₃-C₁₄)cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹,R⁸ C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹, R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹,R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹, R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹,R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹, R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹,R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹;

[0394] R⁸ is H, (C₁-C₈)-alkyl, (C₃-C₁₄)Cycloalkyl,(C₃-C₁₄)cycloalkyl-C₁-C₈)-alkyl, (C₅-C₁₄)-aryl or(C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine;

[0395] R⁹ is a direct linkage or (C₁-C₈)-alkanediyl;

[0396] R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹, P(O)(R¹¹)_(n) or afour-membered to eight-membered, saturated or unsaturated heterocyclewhich contains 1, 2, 3 or 4 heteroatoms from the group N. O and S, suchas tetrazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;

[0397] R¹¹ is OH, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₈)-alkoxy,(C₅-C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂,mono-ordi-((C₁-C₈)-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkylamino,(C₁-C₈)dialkylaminocarbonylmethyloxy,(C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethyloxy or(C₅-C₁₄)-arylamino or the radical of an L-amino acid or O-amino acid;

[0398] R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, H,(C₁-C₁₀)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹,R⁸OC(O)R⁹, R⁸R⁸NR⁹, R⁸—(C₅-C₁₄)-aryl-R⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹,R⁸N(R²)C(O)R⁹, R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²)—NR²,R²R³N—C(═NR²), ═O, or ═S;

[0399] where two adjacent substituents from R¹² to R¹⁵ can also togetherbe —OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—;

[0400] Y is NR², O or S;

[0401] n is 1 or 2;

[0402] p and q are, independently of each other, 0 or 1;

[0403] in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts,

[0404] with compounds being excepted in which E

[0405] a) is a 6-membered aromatic ring system which can contain up to 4N atoms and which can be substituted by from 1 to 4 identical ordifferent arbitrary substituents, or

[0406] b) is 4-methyl-3-oxo-2,3,4,5-tetrahydro-1-H-1,4-benzodiazepine.

[0407] A template from the series of fibrinogen receptor antagonists isunderstood to mean the central part of the molecular structure (of afibrinogen receptor antagonist) to which, in the case of the fibrinogenreceptor antagonists, a basic group and an acidic group are linked byway of spacers, with the basic and/or acidic group being present inprotected form (prodrug) where appropriate.

[0408] In the fibrinogen receptor antagonists, the basic group isgenerally an N-containing group, such as amidine or guanidine, while theacidic group is generally a carboxyl function, with it being possiblefor the basic group and the acidic group to be present in each case inprotected form.

[0409] A fibrinogen receptor antagonist is an active compound whichinhibits the binding of fibrinogen to the blood platelet receptorGPIIbIIIa.

[0410] A fibrinogen receptor antagonist comprises a central part(template) to which a basic group and an acidic group are linked by wayof spacers, with the basic group and/or acidic group being present inprotected form (prodrg), where appropriate.

[0411] Alkyl radicals may be straight-chain or branched. This alsoapplies if they carry substituents or appear as the substituents ofother radicals, for example in alkoxy, alkoxycarbonyl or aralkylradicals. Examples of suitable (C₁-C₁₀-alkyl radicals are: methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, isopropyl,isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl,sec-butyl and tert-pentyl. Preferred alkyl radicals are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0412] Alkenyl and alkynyl radicals may also be straight-chain orbranched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl,butenyl and 3-methyl-2-butenyl, while examples of alkynyl radicals areethynyl, 1-propynyl or propargyl.

[0413] Cycloalkyl radicals may be monocyclic or polycyclic, e.g.bicyclic or tricyclic. Examples of monocyclic cycloalkyl radicals arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and cyclododecyl which, however, can also be substituted by,for example, (C₁-C₄)-alkyl. 4-Methylcyclohexyl and2,3-dimethylcyclopentyl may be mentioned as examples of substitutedcycloalkyl radicals.

[0414] Cyclodecane and cyclododecane are examples of parent substancesof the monocyclic (C₁₀-C₁₄)-cycloalkyl radicals in R⁴, R⁵, R⁶ and R⁷.

[0415] Bicyclic and tricyclic cycloalkyl radicals may be unsubstitutedor substituted, in any suitable position, by one or more oxo groupsand/or one or more identical or different (C₁-C₄)-alkyl groups, e.g.methyl groups or isopropyl groups, preferably methyl groups. The freebond of the bicyclic or tricyclic radical can be located in any positionin the molecule; the radical can consequently be bonded via a bridgeheadatom or via an atom in a bridge. The free bond can also be located inany stereochemical position, for example in an exo position or an endoposition.

[0416] An example of a bicyclic ring system is decalin(decahydronaphthalene), while an example of a system substituted by anoxo group is 2-decanone.

[0417] Examples of parent substances of bicyclic ring systems arenorbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane andbicyclo[3.2.1]octane. An example of a system which is substituted by anoxo group is camphor. (=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

[0418] Examples of parent substances of tricyclic systems are twistane(=tricyclo[4.4.0.0^(3,8)]decane, adamantane(=tricyclo[3.3.1.1^(3,7)]decane), noradamantane(=tricyclo[3.3.1.0^(3,7)]-nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo[5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo[5.5.1.0^(3,11)]tridecane.

[0419] Examples of parent substances of tricyclic (C₁₀-C₁₄)-cycloalkylradicals in R⁴, R⁵, R⁶ and R⁷ are twistane(=tricyclo[4.4.0.0.^(3,8)]decane, adamantane(=tricyclo[3.3.1.1.^(3,7)]nonane), tricyclo[5.3.2.0^(4,9)]dodecane,tricyclo[5.4.0.0^(2,9)]undecane or tricyclo[5.5.1.0^(3,11)]tridecane.

[0420] Halogen is fluorine, chlorine, bromine or iodine.

[0421] Examples of 6-membered aromatic ring systems are phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl and tetrazinyl.

[0422] Aryl is, for example, phenyl, naphthyl, biphenylyl, anthryl orfluoroenyl, with 1-naphthyl, 2-naphthyl and, in particular, phenyl beingpreferred. Aryl radicals, in particular phenyl radicals, may besubstituted, once or more than once, preferably once, twice or threetimes, by identical or different radicals from the group consisting of(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, such as fluorine, chlorine andbromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy,—OCH₂CH₂O—, —OC(CH₃)₂O—, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R¹⁷O)₂P(O),(R¹⁷O)₂P(O)—O— or tetrazolyl, where R¹⁷ is H, (C₁-C₁₀)-alkyl,(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl.

[0423] In monosubstituted phenyl radicals, the substituent can belocated in the 2, 3 or 4 position, with the 3 and 4 positions beingpreferred. If phenyl is substituted twice, the substituents can be inthe 1, 2 or 1, 3 or 1,4 positions relative to each other. The twosubstituents in phenyl radicals which are substituted twice arepreferably, arranged in the 3 and 4 position, based on the linkage site.

[0424] Aryl groups can also be monocyclic or polycyclic aromatic ringsystems in which from 1 to 5 carbon atoms can be replaced by from 1 to 5heteroatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl or (arbolinyl, or a benzo-fused,cyclopenta-, cyclohexa- or cyclohepta-fused derivative of theseradicals. These heterocycles can be substituted by the same substituentsas the abovementioned carbocyclic aryl systems.

[0425] Of these aryl groups, preference is given to monocyclic orbicyclic aromatic ring systems which have from 1 to 3 heteroatoms fromthe group N, O and S and which can be substituted by from 1 to 3substituents selected from the group consisting of (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, F, Cl, NO₂, NH₂, CF₃, OH, (C₁-C₄)-alkoxycarbonyl,phenyl, phenoxy, benzyloxy or benzyl.

[0426] In this context, particular preference is given to monocyclic orbicyclic aromatic 5-membered to 10-membered ring systems which have from1 to 3 heteroatoms from the group N, O and S and which can besubstituted by from 1 to 2 substituents from the group consisting of(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, phenyl, phenoxy, benzyl or benzyloxy.

[0427] L- or D-amino acids can be natural or unnatural amino acids.α-Amino acids are preferred. The following may be mentioned by way ofexample (cf. Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart,1974):

[0428] Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib,Ala, βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu,Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap,Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys,hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp,hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys,βLys, ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe,Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser,Thi, βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val,tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine(Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia),2,2-diphenylaminoacetic acid, 2(p-tolyl)-2-phenylaminoacetic acid and2-(p-chlorophenyl)aminoacetic acid; and also:

[0429] pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid;1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1^(6,9)]decane-3-carboxylic acid;

[0430] decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid,all of which can optionally be substituted (see the following formulae):

[0431] The heterocycles on which the abovementioned radicals are basedare disclosed, for example, in U.S. Pat. Nos. 4,344,949; 4,374,847;4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164;EP-A 89,837; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A111,873; EP-A 271,865 and EP-A 344,682.

[0432] In addition, the amino acids can also be present as esters oramides, such as methyl esters, ethyl esters, isopropyl esters, isobutylesters, tert-butyl esters, benzyl esters, unsubstituted amide,ethylamide, semicarbazide or ω-amino-(C₂-C₈)-alkylamide.

[0433] Functional groups of the amino acids may be present in protectedform. Suitable protecting groups, such as urethane protecting groups,carboxyl protecting groups and side-chain protecting groups, aredescribed in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 andin Büllesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35., ThoseWhich may, in particular, be mentioned are:. Aloc, Pyoc, Fmoc, Tcboc, Z,Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂), Z(Hal_(n)), Bobz, Iboc, Adpoc,Mboc, Acm, tertbutyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.

[0434] Physiologically tolerated salts of the compounds of the formula Iare, in particular, pharmaceutically utilizable or nontoxic salts. Suchsalts are formed, for example, from compounds of the formula I whichcontain acidic groups, e.g. carboxyl, with alkali metals or alkalineearth metals, such as Na, K, Mg and Ca, and also with physiologicallytolerated organic amines, such as triethylamine, ethanolamine ortris-(2-hydroxyethyl)amine. Compounds of the formula I which containbasic groups, e.g. an amino group, an amidino group or a guanidinogroup, form salts with inorganic acids, such as hydrochloric acid,sulfuric acid or phosphoric acid, and with organic carboxylic acids orsulfonic acids, such as acetic acid, citric acid, benzoic acid, maleicacid, fumaric acid, tartaric acid, lactic acid, methanesulfonic acid orp-toluenesulfonic acid.

[0435] The novel compounds of the formula I may contain optically activecarbon atoms, which, independently of each other, can have R or Sconfigurations, and they consequently may be present in the form of pureenantiomers or pure diastereomers or in the form of enantiomericmixtures or diastereomeric mixtures. The present invention relates bothto pure enantiomers and enantiomeric mixtures in all proportions and todiastereomers and diastereomeric mixtures in all proportions.

[0436] The novel compounds of the formula I may be present,independently of each other, as E/Z isomeric mixtures. The presentinvention relates both to pure E and Z isomers and to E/Z isomericmixtures. Diastereomers, including E/Z isomers, can be separated intothe individual isomers by means of chromatography. Racemates can beseparated into the two enantiomers either by means of chromatography onchiral phases or by means of racemate resolution.

[0437] In addition to this, the novel compounds of the formula I maycontain mobile hydrogen atoms, that is they may be present in differenttautomeric forms. The present invention also relates to all thesetautomers.

[0438] Preference is given to compounds of the formula I which areselective vitronectin X receptor antagonists, particularly in relationto the fibrinogen receptor, i.e. which are stronger inhibitors of thevitronectin receptor than of the fibrinogen receptor.

[0439] Preference is given, in particular, to compounds of the formula Iwhich are selective vitronectin receptor antagonists and in which thedistance between R¹⁰ and the first N atom in A is from 12 to 13 covalentbonds along the shortest route between these atoms, as depicted below,by way of example, for

[0440] A=

[0441] and R¹⁰=COOH:

[0442] Preference is also given to compounds of the formula I in whichat least one radical from the group R⁴, R⁵, R⁶ and R⁷ is a lipophilicradical.

[0443] Examples of lipophilic radicals in the group R⁴, R⁵, R⁶ and R⁷are neopentyl, cyclohexyl, adamantyl, cyclohexyl-(C₁-C₈)-alkyl,adamantyl-(C₁-C₈)-alkyl, phenyl, naphthyl, phenyl-(C₁-C₈)-alkyl,naphthyl-C₁-C₈)-alkyl, cyclohexylmethylcarbonylamino,1-adamantylmethyloxycarbonylamino or benzyloxycarbonylamino, or,generally, radicals in which R⁸ is, for example, neopentyl, cyclohexyl,adamantyl, cyclohexyl-(C₁-C₈)-alkyl, adamantyl-(C₁-C₈)-alkyl, phenyl,naphthyl or phenyl-(C₁-C₈)-alkyl.

[0444] Preference is furthermore given to compounds of the formula I inwhich:

[0445] A is the radical

[0446] is a 5-membered to 10-membered monocyclic or polycyclic, aromaticor nonaromatic ring system which can contain from 1 to 4 heteroatomsfrom the group consisting of N, O and S and which can optionally besubstituted, once or more than once, by R¹², R¹³, R¹⁴ and R¹⁵;

[0447] B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₈)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)— —NR²—C(O)—NR²—,—NR²—S(O)—, —NR²—S(O)₂—, —O— or —CR²═CR³— which can in each case besubstituted, once or twice, by (C₁-C₆)-alkyl;

[0448] D is a direct linkage, (C₁-C₈)-alkanediyl, (C₅-C₈)-arylene, —O—,NR²—, —CO—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —S(O)₂—,—S(O)₂—NR²—, —NR²—S(O)₂—, —S—, —CR²═CR³— or —C≡C— which can in each casebe substituted, once or twice, by (C₁-C₈)-alkyl, —CR²═CR³— or(C₅-C₆)-aryl, with it not being possible for D to be —CO—NR²—, —C(O)O—,SO₂— or —S(O)₂—NR²— when B is a direct linkage;

[0449] E is a template which is selected from the fibrinogen receptorantagonist group and which is taken from:

[0450] U.S. Pat. No. 5,250,679, Oct. 5, 1993, Blackburn, B. K. et al.

[0451] U.S. Pat. No. 5,403,836, Apr. 4, 1995, Blackburn, B. K et al.

[0452] U.S. Pat. No. 5,565,449, Oct. 15, 1996, Blackburn, B. K et al.

[0453] WO 93108174, Oct. 15, 1991, Blackburn, B. K et al.

[0454] WO 95/04057, Feb. 9, 1995, Blackburn, B. K et al.

[0455] EP 0 655 439, Nov. 9, 1994, Denney, M. L. et al.

[0456] WO 94/18981, Sep. 1, 1994, Claremon, D. A et al.

[0457] WO 94/08962, Apr. 28, 1994, Harmann, G. D. et al.

[0458] EP 0 668 278, Feb. 14, 1995, Juraszyk, H. et al.

[0459] WO 94/12478, Jun. 9, 1994, Keenan, E. Mc. C. et al.

[0460] F is defined like D;

[0461] G is

[0462] R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl,which is optionally substituted, once or more than once, by fluorine,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl(C₁-C₆)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

[0463] R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine,OH, (C₁-C₈)-alkyl. (C₅-C₁₄)cycloalkyl, (C₅-C₁₄)cycloalkyl-(C₁-C₈)-alkyl,or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸-(C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹,R⁸R⁸NR⁹;

[0464] R⁸N(R²)C(O)OR⁹, R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹, R⁸C(O)R⁹,R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹.R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹;

[0465] R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₁₄)cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl or(C₁-C₁₂)-aryl-(C₁-C₆)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine;

[0466] R⁹ is a direct linkage or (C₁-C₆)-alkanediyl;

[0467] R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹, P(O)(R¹¹)_(n) or afour-membered to eight-membered, saturated or unsaturated heterocyclewhich contains 1, 2, 3 or 4 heteroatoms from the group N, O and S;

[0468] R¹¹ is OH, (C₁-C₆)-alkoxy, (C₅-C₁₂)-aryl-(C₁-C₆)-alkoxy,(C₅-C₁₂)-aryloxy, (C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₂)-aryl-C₁-C₆)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₆)-alkyl)-amino, (C₅-C₁₂)-aryl-(C₁-C₆)-alkylamino,(C₁-C₆)dialkylaminocarbonylmethyloxy;

[0469] R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, H,(C₁-C₈)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl,(C₅-C₁₂)-aryl, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹,R⁸OC(O)R⁹, R⁸-(C₅-C₁₂)-aryl-R⁹, R⁸R⁸NR⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹,R⁸N(R²)C(O)R⁹, R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²),R²R³N—C(═NR²)—NR², ═O or ═S;

[0470] where two adjacent substituents from R¹² to R¹⁵ can also togetherbe —OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—;

[0471] Y is NR², O or S;

[0472] n is 1 or 2;

[0473] p and q are, independently of each other, 0 or 1;

[0474] in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

[0475] Particular preference is given to compounds of the formula I inwhich:

[0476] A is one of the radicals

[0477] B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene,(C₅-C₆)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—S(O)₂—, —O— or—CR²═CR³—, which can in each case be substituted, once or twice, by(C₁-C₆)-alkyl;

[0478] D is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene, —O—,—NR²—, 5-NR²—C(O)— —C(O)NR²—, —NR²—C(O)—NR²—, —OC(O)—S(O)₂—NR²—,—NR²—S(O)₂— or —CR²═CR³—, which can in each case be substituted, once ortwice, by (C₁-C₆)-alkyl, with it not being possible for D to be—C(O)NR²— or —S(O)₂—NR²— when B is a direct linkage;

[0479] E a) is a template from WO 93/08174, U.S. Pat. Nos. 5,250,679,5,403,836 or 5,565,449, specifically:

[0480] where R^(1a), R^(2a), R^(20a), R^(21a), and R^(22a) are definedlike R¹, R², R²⁰, R²¹ and R in U.S. Pat. No. 5,403,836, column 249,lines 9-22; and column 252, line 66 to column 253, line 68, andconsequently

[0481] R^(1a) and R^(2a) are, independently of each other, from one tothree groups from the series consisting of hydrogen, halogen, cyano,carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido,thioureido, hydroxyl, mercapto or sulfonamido, or an; optionallysubstituted radical from the group consisting of C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C₁₄-aryl,C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-alkyloxy, C₆-C₁₄-aryloxy andC₁-C₁₂-acylamino, where the substituents are a radical from the groupconsisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy;

[0482] R^(20a) is hydrogen, halogen (fluorine, chlorine, bromine oriodine), C₁-C₄ alkoxy, C₁-C₄-alkyl, phenyl, benzyl orhalogen-C₁-C₄-alkyl,

[0483] R^(21a) and R^(22a) are, independently of each other,

[0484] 1. hydrogen

[0485] 2. (C₁-C₁₂)-alkyl

[0486] 3. (C₆-C₁₄)-aryl,

[0487] 4. (C₃-C₁₄)-cycloalkyl,

[0488] 5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,

[0489] 6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)cycloalkyl, where the radicals definedunder 2. to 6. can be substituted by one or more radicals from the groupconsisting of

[0490] halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

[0491] R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;

[0492] C₃-C₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can be optionallysubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

[0493] R²⁵ and R²⁶ are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

[0494] R²⁵ and R²⁶ together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

[0495] 7. Q²-L³ where

[0496] Q² is hydrogen or Q¹; and

[0497] L³ is a chemical bond, L¹ or L²;

[0498] Q¹ is a substituted or unsubstituted, positively charged,nitrogen-containing radical,

[0499] L¹ is a divalent radical which contains from 3 to 9 methylenegroups, where from one to all the methylene groups can be replaced withone or more alkene groups, alkyne groups, aryl groups or functionalgroups containing heteroatoms from the group consisting of N, O or S,and

[0500] L² is an optionally substituted, divalent radical;

[0501] where preferred radicals for Q¹, L¹ and L² are those radicals asdescribed in U.S. Pat. No. 5,403,836 in column 249, line 27 to column251, line 6 (Q¹), column 251, line 7 to column 252, line 18 (L¹) andcolumn 252, lines 1945 (L²);

[0502] and R^(22b) is defined like R²² in U.S. Pat. No. 5,565,449,column 296, line 38 to column 297, line 38, and is:

[0503] 1. hydrogen

[0504] 2. (C₁-C₁₂)-alkyl

[0505] 3. (C₆-C₁₄)-aryl,

[0506] 4. (C₃-C₁₄)cycloalkyl,

[0507] 5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,

[0508] 6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)-Cycloalkyl, where the radicals definedunder 2. to 6. can be substituted by one or more radicals from the groupconsisting of

[0509] halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

[0510] R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can optionally besubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

[0511] R²⁵ and R²⁶ are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

[0512] R²⁵ and R²⁶ together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

[0513] 7. Q²-L³, where

[0514] Q² is hydrogen or Q¹; and

[0515] L³ is a chemical bond, L¹ or L²;

[0516] Q¹ is a substituted or unsubstituted, positively charged,nitrogen-containing radical,

[0517] L¹ is a divalent radical which contains from 3 to 9 methylenegroups, where from one to all the methylene groups can be replaced withone or more alkene radicals, alkyne radicals, aryl radicals orfunctional groups containing heteroatoms from the group consisting of N,O or S, and

[0518] L² is an optionally substituted, divalent radical;

[0519] where preferred radicals for Q¹, L¹ and L² are those radicals asdescribed in U.S. Pat. No. 5,403,836 in column 289, line 9 to column293, line 17 (Q¹), column 293, line 18 to column 295,, line 28 (L¹) andcolumn 295, line 29 to column 296, line 11 (L²);

[0520] or b) is a template from WO 95/04057, specifically:

[0521] where R^(1b) and R^(2b) are defined like R¹ and R² in U.S. Pat.No. 5,403,836, column 249, lines 9-22; and:

[0522] R^(1b) and R^(2b) are, independently of each other, from one tothree groups from the series consisting of hydrogen, halogen, cyano,carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido,thioureido, hydroxyl, mercapto or sulfonamido, or an optionallysubstituted radical from the group consisting of C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C-aryl,C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-alkyloxy, C₆-C₁₄-aryloxy andC₁-C₁₂-acylamino, where the substituents are a radical from the groupconsisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy; and

[0523] R^(25b) and R^(26b) are defined like R²⁵ and R²⁶ in U.S. Pat. No.5,565,449 and:

[0524] R^(25b) and R^(26b) are, independently of each other,

[0525] hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl orC₁-C₆-alkyl-C₁-C₁₀-aryl, or

[0526] R^(25b) and R^(26b) together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

[0527] or c)

[0528] is a template from EP-A 0 655 439, specifically

[0529] where

[0530] (R₂)_(p) is bonded to one or more carbon atoms of the 6-memberedring and is, independently of each other, a radical from the groupconsisting of H, alkyl, halogen-substituted alkyl, hydroxyalkyl,alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxyl, alkoxy,aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen,nitro and sulfo;

[0531] R is (C₁-C₄)-alkyl

[0532] p is an integer from 1 to 3,

[0533] or d)

[0534] is a template from WO 94/12478, specifically

[0535] where R^(3′) is hydrogen, (C₁-C₆)-alkyl or aryl-C₁-C₆-alkyl,

[0536] or e) is a template from WO94/18981, specifically

[0537] in which V is CR^(7a) or N, and

[0538] D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂ or

[0539] in which X is CR^(3a) or N,

[0540] where R^(3a) is CN, C(O)N(R^(7a))R^(8a),

[0541] in which V is CR^(7a) or N, and

[0542] D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂ or

[0543] in which X is CR^(3a) or N, in which

[0544] R^(3a) is CN, C(O)N(R^(7a))R^(8a),

[0545] where Y³ is O or H₂, and

[0546] R^(7a) is hydrogen; C₁-C₄-alkyl which is optionally substitutedby OH or (C₁-C₄)-alkoxy; C₂-C₆-alkenyl which is optionally substitutedby (C₁-C₄)-alkoxy; or OH(C₁-C₄)-alkylaryl; or aryl which is optionallysubstituted by identical or different radicals from the group consistingof halogen, (C₁-C₄)-alkoxy, hydroxyl or (C₁-C₄)-alkyl,

[0547] R^(8a) is hydrogen or C₁-C₄-alkyl,

[0548] n is an integer from 0 to 7, and

[0549] n′ is an integer from 0 to 3;

[0550] or f) is a template from EP-A 0531 883, specifically

[0551] where:

[0552] X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)— group,where

[0553] R^(2b) is a hydrogen atom, a straight-chain or branched alkylgroup having from 1 to 15 carbon atoms, a straight-chain or branchedalkenyl or alkynyl group having in each case from 3 to 10 carbon atoms,where the double bond or triple bond cannot connect directly to thenitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each casefrom 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, analkyl group having from 2 to 6 carbon atoms which is substituted, fromthe 1 position to the nitrogen atom of the —NR^(2b)— group onwards, byan R^(3b)O, (R^(3b))₂N—, R^(4b)CO—NR^(3b)—, alkylsulfonyl-NR³—,arylsulfonyl-NR^(3b)—, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group having from 1 to 6 carbon atoms which issubstituted by one or two aryl groups, R^(6b)OCO—, (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—CO-alkylene-NR₃—CO—,(R^(3b))₂N—CO-alkylene-NR^(3b)—CO— or R^(5b)CO-alkylene-NR^(3b)CO—group, in which R^(3b) and R^(5b) are defined as indicated below andR^(6b) is a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkylgroup,

[0554] Y′ is an NO-group, a nitrogen atom or a methine group which isoptionally substituted by an alkyl group,

[0555] Z₁, Z₂, Z₃ and Z₄, which can be identical or different, aremethine groups, carbon atoms, imino groups or nitrogen atoms, where atleast one of the radicals Z₁ to Z₄ has to contain a carbon atom, and oneor two methine groups which are adjacent to a nitrogen atom can in eachcase be replaced by carbonyl groups,

[0556] Z₅ and Z₆ are in each case a carbon atom, or else one of theradicals Z₅ or Z₆ is a nitrogen atom and the other of the radicals Z₅ orZ₆ is a carbon atom,

[0557] R^(3b) is a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkylgroup,

[0558] R^(4b) is a hydrogen atom, an alkyl or alkoxy group having ineach case from 1 to 6 carbon atoms, or an aryl or aralkyl group havingfrom 1 to 6 carbon atoms in the alkyl moiety, and

[0559] R^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an amino group which issubstituted by an R₃, R₄CO—, alkylsulfonyl or arylsulfonyl group, whereR₃ and R₄ are defined as mentioned above;

[0560] F is a direct linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—,—NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—, —C(O)O—, —CO—, —S(O)₂—, —S(O)₂—NR²—,—NR²—S(O)₂—, —CR²═CR³, —C≡C— which can in each case be substituted, onceor twice, by (C₁-C₆)-alkyl;

[0561] G is

[0562] R² and R³ are, independently of each other, H, (C₁-C₆)-alkylwhich is optionally substituted, once or more than once, by fluorine,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, (C₅C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹;

[0563] R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H, fluorine,OH, (C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₁-C₁₄)cycloalkyl-(C₁-C₆)-alkyl, or R⁸OR⁹, R⁸CO²R⁹, R⁸OC(O)R⁹,R⁸C₅-C₁₀)-aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹, R⁸NHC(O)OR⁹, R⁸S(O)_(n)NHR⁹,R⁸OC(O)NHR⁹, R⁸C(O)NHR⁹, R⁸C(O)R⁹, R⁸NHC(O)NHR⁹, R⁸NHS(O)_(n)NHR⁹,R⁸NHC(O)R⁹ or R⁸NHS(O)_(n)R⁹, where at least one radical from the groupR⁴, R⁵, R⁶ and R⁷ is a lipophilic radical, such asbenzyloxycarbonylamino, cyclohexylmethylcarbonylamino etc.;

[0564] R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl or(C₅-C₁₀)-aryl<C₁-C₄)-alkyl, where the alkyl radicals can be substitutedby from 1 to 6 fluorine atoms;

[0565] R⁹ is a direct linkage or (C₁-C₆)-alkanediyl;

[0566] R¹⁰ is C(O)R¹¹;

[0567] R¹¹ is OH, (C₁-C₆)-alkoxy, (C₅-C₁₀)-aryl-(C₁-C₆)-alkoxy,(C₅-C₁₀)-aryloxy, (C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₀)-aryl-(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi(C₁-C₆)-alkyl)-amino;

[0568] R¹² is H, (C₁-C₆)-alkyl which is optionally substituted, once ormore than once, by fluorine, (C₃-C₆)-cycloalkyl,(C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, H₂N, R⁸OR⁹, R⁸OC(O)R⁹, R⁸-(C₅-C₁₀)-aryl-R⁹,R⁸R⁸NR⁹, R⁸NHC(O)R⁹, R⁸C(O)NHR⁹, H₂N—C(═NH)—, H₂N—C(═NH)—NH— or ═O;

[0569] where two adjacent substituents R¹² can together also be —OCH₂O—or —OCH₂CH₂O—;

[0570] Y is NR² O or S;

[0571] n is 1 or 2; and

[0572] p and q are, independently of each other, 0 or 1;

[0573] in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

[0574] Very particular preference is given to compounds of the formula Iin which:

[0575] A is one of the radicals.

[0576] B is a direct linkage, (C₁-C₄)-alkanediyl, phenylene,pyridindiyl, thiophenediyl, furandiyl, cyclohexylene, cyclopentylene,—C≡C— or —CR²═CR³— which can in each case be substituted, once or twice,by (C₁-C₄)-alkyl;

[0577] D is a direct linkage, (C₁-C₄)-alkanediyl or phenylene, —O—,—NR²—, —NR²—C(O)—, —C(O)—NR²—, —NR²—S(O)₂, —NR²—C(O)—NR²— or —CR²═CR³—which can in each case be substituted, once or twice, by (C₁-C₄)-alkyl,with it not being possible for D to be —C(O)—NR²— when B is a directlinkage;

[0578] E a) is a template from WO 93/08174, U.S. Pat. Nos. 5,250,679,5,403,836 or 5,565,449, specifically:

[0579] where R^(1a), R^(20a), R^(21a), R^(22a) and R^(22b) are in thiscase:

[0580] R^(1a) is, independently of each other, from one to three groupsfrom the series consisting of hydrogen and halogen (fluorine, chlorine,bromine or iodine);

[0581] R^(20a) is hydrogen;

[0582] R^(21a) and R^(22a) are, independently of each other,

[0583] 1. hydrogen,

[0584] 2. (C₁-C₆)-alkyl,

[0585] 3. (C₆-C₁₂)-aryl,

[0586] 4. (C₆-C₁₂)-cycloalkyl,

[0587] 5. (C₁-C₆)-alkyl-(C₆-C₁₂)-aryl,

[0588] 6. (C₁-C₆)-alkyl-(C₆ ₁₂)-cycloalkyl, where the radicals definedunder 2. to 6. can be substituted by one or more radicals from the groupconsisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide,(C₁-C₆)-alkyl, (C₆-C₁₂)-aryl, benzyl or (C₆-C₁₂)-cycloalkyl;

[0589] R^(22b) is 1. hydrogen,

[0590] 2. (C₁-C₁₂)alkyl

[0591] 3. (C₆-C₁₄)-aryl,

[0592] 4. (C₃-C₁₄)-cycloalkyl,

[0593] 5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,

[0594] 6. (C₁-C₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals definedunder 2. to 6. can be substituted by one or more radicals from the groupconsisting of

[0595] halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl;carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where

[0596] R^(24a) is a radical from the group consisting of C₁-C₈-alkoxy;C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-Cs-alkoxy;acylamino-C₁-C₈-alkoxy, such as acetylaminoethoxy,nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; orC₆-C₁₂-aryl(C₁-C₈-alkoxy, where the aryl group can be optionallysubstituted by from one to three radicals selected from the groupconsisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy;

[0597] R²⁵ and R²⁶ are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

[0598] R²⁵ and R²⁶ together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

[0599] 7. Q²-L³, where

[0600] Q² is hydrogen or Q¹; and

[0601] L³ is a chemical bond or L¹;

[0602] Q¹ is an amino, amidino, aminoalkylenimino, iminoalkylenamino orguanidino group, preferably an amidinogroup;

[0603] L¹ is C₆-C₁₄-aryl-C₂-C₄-alkynylene; C₆-C₁₄-aryl-C₁-C₃-alkylene;C₆-C₁₄-aryl-C₁-C₃-alkyloxyene or —R^(14c)—CO—NR^(6c)R^(15c), where

[0604] R^(6c) is hydrogen, C₁-C₄-alkoxy, C₁-C₄-alkyl orhalogen-C₁-C₄-alkyl;

[0605] R^(14c) is a chemical bond, C₁-C₈-alkylene, C₃-C₇-cycloalkylene,C₂-C₅-alkenylene, C₃-C₅-alkynylene, C₆-C₁₀-arylene,C₁-C₃-alkyl-C₆-C₁₂-arylene, C₁-C₂-alkyl-C₆-C₁₀-aryl-C₁-C₂-alkylene,C₆-C₁₀-aryl-C₁-C₂-alkylene or C₆-C₁₀-aryloxy-C₁-C₂-alkylene, and

[0606] R^(15c) is a chemical bond, C₁-C₄-alkylen, C₂-C₄-alkenylen,C₂-C₄-alkynylen, C₆-C₁₀-arylen or C₁-C₃-alkyl-C₆-C₁₂-arylen;

[0607] or b) is a template from WO 95/04057, specifically:

[0608] where R^(1b), R^(2b), R^(25b) and R^(26b) are in this case:

[0609] R^(1b) and R^(2b) are independently of each other, from one tothree groups from the series consisting of hydrogen and halogen(fluorine, chlorine, bromine or iodine); and

[0610] R²⁵ and R²⁶ are, independently of each other, hydrogen,C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or

[0611] R^(25b) and R^(26b) together form a trimethylene, tetramethylene,pentamethylene or 3-oxopentamethylene radical;

[0612] or c) is a template from EP 0 655 439, specifically:

[0613] or d) is a template from WO 94/12478, specifically:

[0614] or e) is a template from WO 94118981, specifically:

[0615] where Y³, V and D^(a) are defined as described above;

[0616] or f) is a template from EP 0 531 883, specifically:

[0617] where:

[0618] X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)-group,where

[0619] R^(2b) is a hydrogen atom, a straight-chain or branched alkylgroup having from 1 to 15 carbon atoms, a straight-chain or branchedalkenyl or alkynyl group having in each case from 3 to 10 carbon atoms,where the double bond or triple bond cannot connect directly to thenitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each casefrom 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, analkyl group having from 2 to 6 carbon atoms which is substituted, fromthe β position to the nitrogen atom of the —NR^(2b)-group onward, by, anR^(3b)O—, (R^(3b))₂N—, R^(4b)CO—NR^(3b)—, alkylsulfonyl-NR^(3b)—,arylsulfonyl-NR^(3b), alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group having from 1 to 6 carbon atoms which issubstituted by one or two aryl groups, R^(6b)OCO—, (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—OC-alkylene-NR^(3b)CO,(R^(3b))₂N-CO-alkylene-NR^(3b)—CO— or R^(5b)CO-alkylene-NR^(3b)—CO—group, in which R^(3b) and R^(5b) are defined as indicated below andR^(6b) is a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkylgroup,

[0620] Y′ is an NO-group, a nitrogen atom or a methine group which isoptionally substituted by an alkyl group,

[0621] Z₁, Z₂, Z₃ and Z₄, which can be identical or different, aremethine groups, carbon atoms, imino groups or nitrogen atoms, where atleast one of the radicals Z₁ to Z₄ has to contain a carbon atom, and oneor two methine groups which are adjacent to a nitrogen atom can in eachcase be replaced by carbonyl groups,

[0622] Z₅ and Z₆ are in each case a carbon atom, or else one of theradicals Z₅ or Z₆ is a nitrogen atom and the other of the radicals 4 or6 is a carbon atom,

[0623] R^(3b) is a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkylgroup,

[0624] R^(4b) is a hydrogen atom, an alkyl or alkoxy group having ineach case from 1 to 6 carbon atoms, or an aryl or aralkyl group havingfrom 1 to 6 carbon atoms in the alkyl moiety, and

[0625] R^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an imino group which issubstituted by an R^(3b), R^(4b)CO, alkylsulfonyl or arylsulfonyl group,where R^(3b) and R^(4b) are defined as mentioned above,

[0626] F is a direct linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—,—NR²—CO—, —NR²—C(O)—NR²—, —S(O)₂—NR², —NR² S(O)₂—, —CR²═CR³, or —C≡C—which can in each case be substituted, once or twice, by (C₁-C₄)-alkyl;

[0627] G is

[0628] R² and R³ are, independently of each other, H, (C₁-C₄)-alkyl,trifluoromethyl, pentafluoroethyl, (C₅-C₆)cycloalkyl,(C₅-C₆)-cycloalkyl-C₁-C₄)-alkyl, phenyl or benzyl;

[0629] R⁴ is (C₁₀-C₁₄)-cycloalkyl, (C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl,or R¹⁶OR⁹, R¹⁶NHR⁹, R¹⁶NHC(O)OR⁹, R¹⁶S(O)_(n)NHR⁹, R¹⁶OC(O)NHR⁹,R¹⁶C(O)NHR⁹, R¹⁶C(O)R⁹, R¹⁶NHC(O)R⁹ or R¹⁶NHS(O)_(n)R⁹;

[0630] R⁵ is H, (C₁-C₆)-alkyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, trifluoromethyl, pentafluoroethyl,phenyl or benzyl;

[0631] R⁸ is H, (C₁-C₄)-alkyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, phenyl, benzyl, trifluoromethyl orpentafluoroethyl;

[0632] R⁹ is a direct linkage or (C₁-C₄)-alkanediyl;

[0633] R¹⁰ is C(O)R¹¹;

[0634] R¹¹ is OH, (C₁-C₆)-alkoxy, phenoxy, benzyloxy,(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi(C₁-C₆)-alkyl)amino;

[0635] R¹² is H, (C₁-C₄)-alkyl, trifluoromethyl, pentafluoroethyl,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, (C₅-C₆)-aryl,(C₅-C₆)-aryl-(C₁-C₂)-alkyl, H₂N, R⁸R⁸NR⁹, R⁸NHC(O)R⁹, H₂N—C(═NH) orH₂N—C(═NH)—NH—; where two adjacent substituents R¹² can also be —OCH₂O—or —OCH₂CH₂O—;

[0636] R¹⁶ is (C₁₀-C₁₄)-cycloalkyl or (C₁₀-C₁₄)cycloalkyl-(C₁-C₄)-alkylwhich can optionally be substituted, once or twice, by (C₁-C₄)-alkyl,trifluoromethyl, phenyl, benzyl, (C₁-C₄)-alkoxy, phenoxy, benzyloxy, ═Oor mono- or di(C₁-C₄)-alkyl)-amino, where the cycloalkylene radicals arepreferably 1-adamantyl or 2-adamantyl, which can be substituted asdescribed above;

[0637] n is 1 or 2; and

[0638] q is 0 or 1;

[0639] in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.

[0640] Preference is also given to compounds of the formula I, in whichA, B. D, F and G are defined as above for the very particularlypreferred compounds of the formula I and E is a template from WO95/04057, EP 0655 439, WO 94/18981, WO 94/08962, EP 0668 278, WO94/12478 or EP 0531 883, with the latter preferably being defined asabove for the particularly preferred compounds of the formula I, andparticularly preferably being defined as above for the very particularlypreferred compounds of the formula I.

[0641] Another part of the subject-matter of the present invention isthat a fibrinogen receptor antagonist, which is known per se, can beconverted into a selective vitronectin receptor antagonist by replacingthe basic group (with spacer) of a fibrinogen receptor antagonist withthe residue A-B-D, which is defined as in Formula I, with the distancebetween R¹⁰ and the first N atom in A being from 12 to 13 covalent bondsalong the shortest route between these atoms.

[0642] In general, compounds of the formula I can be prepared, forexample during the course of a convergent synthesis, by linking two ormore fragments which can be derived retrosynthetically from the formulaI. When preparing the compounds of the formula I, it can, in a generalmanner, be necessary, during the course of the synthesis, to use aprotecting group strategy which is suited to the synthesis problem totemporarily block functional groups which could lead to undesirablereactions or side reactions in the particular synthesis step, as isknown to the skilled person. The method of fragment linking is notrestricted to the following examples but is generally applicable tosyntheses of the compounds of the formula I.

[0643] For example, compounds of the formula I of the type

A-B-D-E-C(O)NR²-G,

[0644] in which F═C(O)NR², can be prepared by condensing a compound ofthe formula II

A-B-D-E-M  II,

[0645] where M is hydroxycarbonyl, (C₁-C₆)-alkoxycarbonyl or activatedcarboxylic derivatives, such as acid chlorides, active esters or mixedanhydrides, with HNR²-G.

[0646] In order to condense two fragments with the formation of an amidebond, use is advantageously made of the coupling methods, which areknown per se, of peptide chemistry (see, for example, Houben-Weyl,Methoden der Organischen Chemie [Methods of Organic Chemistry], Volumes15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). For this, it is,as a rule, necessary for non-reacting amino groups which are present tobe protected with reversible protecting groups during the condensation.The same applies to carboxyl groups which are not involved in thereaction, which carboxyl groups are preferably employed as(C₁-C₆)-alkyl, benzyl or tert-butyl esters. There is no necessity toprotect amino groups if the amino groups to be generated are stillpresent as nitro or cyano groups and are only formed by means ofhydrogenation after the coupling has taken place. After the coupling hastaken place, the protecting groups which are present are eliminated in asuitable manner. For example, NO₂ groups (guanidino protection),benzyloxycarbonyl groups and benzyl esters can be removed byhydrogenation. The protecting groups of the tert-butyl type areeliminated under acid conditions, while the 9-fluorenylmethyloxycarbonylradical is removed using secondary amines.

[0647] Compounds of the formula I in which R¹⁰=SO₂R¹¹ are prepared, forexample, by oxidizing compounds of the formula I in which R¹⁰=SH usingmethods which are known from the literature (cf. Houben-Weyl, Methodender Organischen Chemie, Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985,pp. 1058ff) to give compounds of the formula I in which R¹⁰ SO₃H, fromwhich the compounds of the formula I in which R¹⁰=SO₂R¹¹ (R¹¹≠OH) arethen prepared directly or by way of corresponding sulfonyl halides bymeans of esterification or formation of an amide bond.Oxidation-sensitive groups in the molecule, such as amino, amidino orguanidino groups, are, if necessary, protected with suitable protectinggroups before performing the oxidation.

[0648] Compounds of the formula I in which R¹⁰=S(O)R¹¹ are prepared, forexample, by converting compounds of the formula I in which R¹⁰=SH intothe corresponding sulfide (R¹⁰=S^(⊖)) and then oxidizing withmeta-chloroperbenzoic acid to give the sulfinic acids (R¹⁰=SO₂H) (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg ThiemeVerlag, Stuttgart 1985, pp. 618f), from which the corresponding sulfinicacid esters or amides, R¹⁰=S(O)R¹¹ (R¹¹≠OH), can be prepared usingmethods which are known from the literature. In a general manner, othermethods known from the literature can also be used to prepare compoundsof the formula I in which R¹⁰=S(O)_(n)R¹¹ (n=1 or 2) (cf. Houben-Weyl,Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag,Stuttgart 1985, pp. 618ff or Vol. E11/2, Stuttgart 1985, pp. 1055ff).

[0649] Compounds of the formula I in which R¹⁰=P(O)(R¹¹)_(n) (n=1 or 2)are synthesized, using methods which are known from the literature (cf.Houben-Weyl, Methoden der Organischen Chemie, Vols. E1 and E2, GeorgThieme Verlag, Stuttgart 1982), from suitable precursors, with it beingnecessary to match the selected synthesis method to the target molecule.

[0650] Compounds of the formula I in which R¹⁰=C(S)R¹¹ can be preparedusing methods known from the literature (cf. Houben-Weyl, Methoden derOrganischen Chemie, Vols. E5/1 and E5/2, Georg Thieme Verlag, Stuttgart1985).

[0651] Compounds of the formula I in which R¹⁰=S(O)_(n)R¹¹ (n=1 or 2),P(O)(R¹¹)_(n) (n=1 or 2) or C(S)R¹¹ may, of course, also be prepared bymeans of fragment linking, as described above, which approach is, forexample, advisable when, for example, a (commercially available)aminosulfonic acid, aminosulfinic acid, aminophosphonic acid oraminophosphinic acid, or derivatives derived therefrom, such as estersor amides, are present in F-G of the formula I.

[0652] Compounds of the formula I in which A-B- is a radical of theformula

[0653] are prepared, using methods which are known from the literature,by reacting compounds of the formula

[0654] with sulfinic or sulfonic acid derivatives of the formula IV,

Q-S(O)_(n)-D-E-F-G  IV

[0655] in which Q is, e.g., Cl or NH₂, in analogy with S. Birtwell etal., J. Chem. Soc. (1946) 491 or Houben Weyl, Methoden der OrganischenChemie, Vol. E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 ff.

[0656] Compounds of the formula I in which B is —NR²—C(O)—NR²—,—NR²—C(O)O— or —NR²—C(O)S— and A has the given meaning are prepared, forexample, by reacting a compound of the formula V

Q-D-E-F-G  V

[0657] in which Q is HNR²—, HO— or HS—, with a suitable carbonic acidderivative, preferably phosgene, diphosgene (trichloromethylchloroformate), triphosgene (bis(trichloromethyl) carbonate), ethylchloroformate, butyl chloroformate, bis(1-hydroxy-1-H-benzotriazolyl)carbonate or N,N′-carbonyldiimidazole in a solvent which is inerttowards the reagents employed, preferably dimethylformamide (DMF),tetrahydrofuran (THF) or toluene, at a temperature of between −20° C.and the boiling point of the solvent, preferably between 0° C. and 60°C., initially to form a substituted carbonic acid derivative of theformula VI,

[0658] in which R is —NR²—, —O— or —S— and Q¹ is chlorine, methoxy,ethoxy, isobutoxy, benzotriazol-1-oxy or 1-imidazolyl, depending on thecarbonic acid derivative, employed.

[0659] The reaction of these derivatives with the monocycle orpolycycle-containing systems of the type VII

[0660] is effected in a protic or aprotic, polar but inert organicsolvent. In this context, methanol, isopropanol or THF, at temperaturesof from 20° C. up to the boiling temperature of these solvents, haveproved to be of value when reacting the methyl esters (Q=OMe) with therespective compounds of the formula VII. Most reactions of compounds ofthe formula VI with salt-free compounds of the formula VII areadvantageously carried out in aprotic, inert solvents such as THF,dimethoxyethane or dioxane. However, when a base (such as NaOH) isemployed, water can also be used as a solvent when compounds of theformula IV are reacted with the compounds VII. When Q=Cl, the reactionis advantageously carried out with the addition of a base as anacid-capturing agent, in order to bind the hydrohalic acid.

[0661] Compounds of the formula I in which F is —R²NC(O)—NR²— or—R²N—C(S)—NR²—, are prepared, for example, by reacting a compound of theformula VIII

A-B-D-E-NHR²  VIII

[0662] H with an isocyanate OCNG or isothiocyanate SCN-G using methodswhich are known from the literature.

[0663] Compounds of the formula I in which F is —C(O)NR²—, —SO₂NR²— or—C(O)O— can be obtained, for example, by reacting

A-B-D-E-C(O)Q or A-B-D-E-SO₂Q

[0664] (Q is a leaving group which can readily be substitutednucleophilically, for example OH, Cl, OMe, etc.) with HR²N-G or HO-G,respectively, using methods known from the literature.

[0665] Compounds of the formula I, in which A is a monocycle orpolycycle of the type

[0666] can be prepared, for example, by

[0667] a) reacting a compound of the formula IX

HR²N-D-E-F-G  IX

[0668] with a monocycle or polycycle of the type

[0669] in which X is a leaving group which can be substitutednucleophilically, for example halogen or SH, —SCH₃, SOCH₃, SO₂CH₃ orHN—NO², using methods which are known from the literature (see, e.g., A.F. Mckay et al., J. Med. Chem. 6 (1963) 587, M. N. Buchman et al., J.Am. Chem. Soc. 71 (1949), 766, F. Jung et al., J. Med. Chem. 34 (1991)1110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391),

[0670] or b) reacting a 1,2-diamino compound of the formula XVII

[0671] with an isothiocyanate of the formula XIII

SCN-B-D-E-F-G  XIII

[0672] to give a thiourea derivative of the formula XVIII

[0673] e.g. in accordance with F. Janssens et al., J. Med. Chem. 28(1985) 1925, which is then converted, as described in that paper or, forexample, in accordance with A. Mohsen et al., Synthesis (1977) 864 or V.Ojka et al., Indian J. Chem. Sec. B 32 (3) (1993) 394, into thecompounds of the formula I in which A=

[0674] or c) reacting a 1 nitro-2-amino compound of the formula XIX

[0675] with an isothiocyanate of the formula XIII to give a thioureaderivative of the formula XX

[0676] which, after reduction of the nitrogroup with Pd/C (cf., e.g., F.Janssens et al., J. Med. Chem. 28 (1985) 1925) as described above, isconverted into compounds of the formula I in which

[0677] A=

[0678] Compounds of the formula I in which A is a monocycle or polycycleof the type

[0679] are obtained using methods which are known from the literature,e.g. from compounds of the formula

[0680] by reaction with compounds of the formula R²—NH-B-D-E-F-Gfollowing M. Yamato, et al., Chem. Pharm. Bull 32(8) (1984) 3053, or,e.g., from 1,2-amincalcohols of the formula XII

[0681] which are initially converted, by reaction with isothiocyanatesof the formula XIII

SCN-B-D-E-F-G  XIII

[0682] into thioureas of the formula XIV

[0683] which are then converted, e.g. as described by H. S. Chang etal., Chem. Lett. 8 (1986)1291 or E. A. Ibrahim et al., J. Heterocycl.Chem. 19(4) (1982) 761, into the compounds of the formula I in which

[0684] A=

[0685] Compounds of the formula I in which A is a monocycle or polycycleof the type

[0686] are obtained using methods which are known from the literature,e.g. from 1,2-aminothiols of the formula XV

[0687] which are initially converted, by reaction with isothiocyanatesof the formula XIII, into the thioureas of the formula XVI

[0688] which are then converted, e.g. as described by J. Garvin et al.,J. Heterocycl. Chem. 28 (1991) 359 into the compounds of the formula Iin which

[0689] A=

[0690] Compounds of the formula I in which D is —C≡C— can be prepared,for example, by reacting a compound of the formula X

X-E-F-G  X

[0691] in which X is I or Br, with a compound of the type A-B-C≡CH in apalladium-catalyzed reaction, as described, for example, in A. Arcadi etal., Tetrahedron Lett. 1993, 34, 2813 or E. C. Taylor et al., J. Org.Chem. 1990, 55, 3222.

[0692] In an analogous manner, compounds of the formula I in which F is—C≡C— can be prepared, for example, by linking compounds of the formulaXI

A-B-D-E-X  XI

[0693] in which X is I or Br, with a compound of the type HC≡C-G in apalladium-catalyzed reaction.

[0694] The fibrinogen receptor antagonist template E is synthesized asdescribed in the relevant patents, patent applications or publications,with functional groups being incorporated into the template, or beingattached to the template, during synthesis of the template orafterwards, preferably during synthesis of the template, which groupspermit the subsequent linking-on of A-B-D and F-G by means of fragmentlinking, as described below, by way of example, for a template from WO94/18981:

[0695] Example of the linking-on of A-B-D and F-G

[0696] Preparation methods which are known from the literature aredescribed, for example, in J. March, Advanced Organic Chemistry, ThirdEdition (John Wiley & Sons, 1985).

[0697] The compounds of the formula I, and their physiologicallytolerated salts, may be administered to animals, preferably to mammalsand, in particular, to humans, as drugs on their own, in mixtures witheach other or in the form of pharmaceutical preparations which permitenteral or parenteral use and which comprise, as the active constituent,an effective dose of at least one compound of the formula I or of a saltthereof, together with customary, pharmaceutically unobjectionablecarrier and auxiliary substances. The preparations normally comprisefrom about 0.5 to 90% by weight of the therapeutically active compound.

[0698] The drugs may be administered orally, for example in the form ofpills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. However, the administration can also be effectedrectally, for example in the form of suppositories, or parenterally, forexample in the form of injection or infusion solutions, microcapsules orrods, percutaneously, for example in the form of ointments or tinctures,or nasally, for example in the form of nasal sprays.

[0699] The pharmaceutical preparations are produced in a manner knownper se, with pharmaceutically inert inorganic or organic carriersubstances being used. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts, etc. can, for example, be used forpreparing pills, tablets, coated tablets and hard gelatin capsules.Examples of carrier substances for soft gelatin capsules andsuppositories are fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Examples of suitable carrier substances forpreparing solutions and syrups are water, sucrose, invert sugar,glucose, polyols, etc. Suitable carrier substances for preparinginjection solutions are water, alcohols, glycerol, polyols, vegetableoils, etc. Suitable carrier substances for microcapsules, implants orrods are mixed polymers of glycolic acid and lactic acid.

[0700] In addition to the active compounds and carrier substances, thepharmaceutical preparations may also comprise additives, such asfillers, extenders, disintegrants, binders, glidants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorants oraromatizing substances, thickeners, diluents or buffering substances,and also solvents or solubilizing agents or agents for achieving a slowrelease effect, and also salts for altering the osmotic pressure,coating agents or antioxidants. They may also comprise two or morecompounds of the formula I or their physiologically tolerated salts;they may furthermore comprise one or more different therapeuticallyactive compounds in addition to at least one compound of the formula I.

[0701] The dose may be varied within wide limits and must be adjusted tothe individual circumstances in each individual case.

[0702] In the case of oral administration, the daily dose may be from0.01 to 100 mg/kg, preferably from 0.1 to 5 mg/kg, particularly from 0.3to 0.5 mg/kg of bodyweight in order to achieve effective results. In thecase of intravenous administration the daily dose also is generally fromabout 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg of bodyweight.Particularly when administering relatively large quantities, the dailydose can be subdivided into several, e.g. 2, 3 or 4, parts which areadministered separately. Where appropriate, it can be necessary todepart from the given daily dose in an upward or downward directiondepending on the individual response.

[0703] Besides as active drug substances the compounds of the formula Imay be used in diagnostic procedures, for example in in vitro diagnoses,or as tools in biochemical research when it is intended to inhibit thevitronectin receptor.

[0704] The inhibition of bone resorption by the novel compounds can bedetermined, for example, using an osteoclast resorption test (PITASSAY), for example in analogy with WO 95/32710. The test methods whichcan be used to determine the antagonistic effect of the novel compoundson the vitronectin receptor α_(V)β₃ are described below.

[0705] Test Method 1:

[0706] Inhibition of the binding of human vitronectin (Vn) to humanvitronectin receptor (VnR) α_(V)β₃ ELISA test.

[0707] 1. Purification of Human Vitronectin

[0708] Human vitronectin is isolated from human plasma and purified byaffinity chromatography using the method of Yatohyo et al., CellStructure and Function, 1988, 23, 281-292.

[0709] 2. Purification of Human Vitronectin Receptor (α_(V)β₃)

[0710] Human vitronectin receptor is isolated from the human placentausing the method of Pytela et al., Methods Enzymol. 1987, 144, 475.Human vitronectin receptor α_(V)β₃ can also be isolated from some celllines (e.g. from 293 cells, which is a human embryonic kidney cell line)which have been cotransfected with DNA sequences for both the subunits,i.e. α_(V) and β₃, of the vitronectin receptor. The subunits areextracted with octyl glycoside and then chromatographed throughconcanavalin A, heparin-Sepharose and S-300.

[0711] 3. Monoclonal Antibodies

[0712] Murine monoclonal antibodies which are specific for the β₃subunit of the vitronectin receptor are prepared using the method ofNewman et al., Blood, 1985, 227-232, or using a similar method.Horseradish peroxidase-conjugated rabbit Fab 2 anti-mouse Fc (anti-mouseFc HRP) was obtained from Pel Freeze (Catalog No. 715 305-1).

[0713] 4. ELISA Test

[0714] Nunc Maxisorp 96-well microtiter plates are coated at 4° C.overnight with a solution of human vitronectin (0.002 mg/ml, 0.05ml/well) in PBS (phosphate-buffered sodium chloride solution). Theplates are washed twice with PBS/0.05% Tween 20 and blocked byincubating (60 min) with bovine serum albumin (BSA, 0.5%, RIA quality orbetter) in Tris-HCl (50 mM), NaCl (100 mM), MgCl₂ (1 mM), CaCl₂ (1 mM),MnCl₂ (1 mM), pH 7. Solutions of known inhibitors and of the testsubstances, in concentrations of from 2×10⁻¹² to 2×10⁻⁶ mol/l, areprepared in assay buffer [BSA (0.5%, RIA quality or better) in Tris-HCl(50 mM), NaCl (100 mM), MgCl₂ (1 mM), CaCl₂ (1 mM), MnCl₂ (1 mM)l pH 7].The blocked plates are emptied and in each case 0.025 ml of thissolution, which contains a defined concentration (from 2×10⁻¹² to2×10⁻⁶) of either a known inhibitor or of a test substance, is added toeach well. 0.025 ml of a solution of the vitronectin receptor in thetest buffer (0.03 mg/ml) is pipetted into each well of the plate and theplate is incubated on a shaker at room temperature for 60-180 min. Inthe meantime, a solution (6 ml/plate) of a murine monoclonal antibodywhich is specific for the β₃ subunit of the vitronectin receptor isprepared in the assay buffer (0.0015 mg/ml). A second rabbit antibody,which is an anti-mouse Fc HRP antibody conjugate, is added to thissolution (0.001 ml of stock solution/6 ml of the murine monoclonalanti-β₃ antibody solution), and this mixture composed of murine anti-β₃antibody and rabbit anti-mouse Fc HRP antibody conjugate is left toincubate during the period of the receptor/inhibitor incubation.

[0715] The test plates are washed 4 times with PBS solution containing0.05% Tween-20, and in each case 0.05 ml/well of the antibody mixture ispipetted into each well of the plate and the plate is incubated for60-180 min. The plate is washed 4 times with PBS/0.05% Tween-20 and thendeveloped with 0.05 ml/well of a PBS solution which contains 0.67 mg/mlo-phenylenediamine and 0.012% H₂O₂. As an alternative,o-phenylenediamine can be used in a buffer (pH 5) which contains Na₃PO₄(50 mM) and citric acid. The color development is stopped with 1 N H₂SO₄(0.05 ml/well). The absorption of each well is measured at 492-405 nmand the data are evaluated using standard methods.

[0716] Test Method 2:

[0717] Inhibition of the binding of kistrin to human vitronectinreceptor (VnR) α_(V)β₃: ELISA test

[0718] 1. Purification of Kistrin

[0719] Kistrin is purified using the methods of Dennis et al., asdescribed in Proc. Natl. Acad. Sci. USA 1989, 87, 2471-2475 andPROTEINS: Structure, Function and Genetics 1993,15, 312-321.

[0720] 2. Purification of Human Vitronectin Receptor (α_(V)β₃) See TestMethod 1.

[0721] 3. Monoclonal Antibodies

[0722] see test method 1.

[0723] 4. ELISA Test

[0724] The ability of substances to inhibit the binding of kistrin tothe vitronectin receptor can be ascertained using an ELISA test. Forthis purpose, Nunc 96-well microtiter plates are coated with a solutionof kistrin (0.002 mg/ml) using the method of Dennis et al., as describedin PROTEINS: Structure, Function and Genetics 1993, 15, 312-321. Thesubsequent experimental implementation of the ELISA test is as describedin test method 1, item 4.

[0725] Test method 3:

[0726] Inhibition of the binding of α_(V)β₃-transfected 293 cells tohuman vitronectin:

[0727] Cell Test

[0728] 293 cells, a human embryonic kidney cell line, which arecotransfected with DNA sequences for the α_(V) and β₃ subunits of thevitronectin receptor α_(V)β₃ are selected for a high rate of expression(>500,000 α_(V)β₃ receptors/cell) using the FACS method. The selectedcells are cultured and re-sorted by FACS in order to obtain a stablecell line (15 D) having expression rates of >1,000,000 copies of α_(V)β₃per cell.

[0729] A Limbro 96-well tissue culture plate having a flat bottom iscoated at 4° C. overnight with human vitronectin (0.01 mg/ml, 0.05ml/well) in phosphate-buffered sodium chloride solution (PBS) and thenblocked with 0.5% BSA. Solutions of the test substances havingconcentrations of from 10⁻¹⁰ to 2×10⁻³ mol/l are prepared inglucose-containing DMEM medium, and in each case 0.05 ml/well of thesolution is added to the plate. The cells which are expressing highlevels of α_(V)β₃ (e.g. 15 D) are suspended in glucose-containing DMEMmedium and the suspension is adjusted to a content of 25,000 cells/0.05ml of medium. 0.05 ml of this cell suspension is then added to each welland the plate is incubated at 37° C. for 90 min. The plate is washed3×with warm PBS in order to remove unbound cells. The bound cells arelysed in citrate buffer (25 mM, pH 5.0) containing 0.25% Triton X-100.The hexose amidase substrate p-nitrophenyl-N-acetyl-1-β-D-glucosaminideis then added and the plate is incubated at 37° C. for 90 min. Thereaction is stopped with a glycine (50 mM)/EDTA (5 mM) buffer (pH 10.4)and the absorption of each well is measured at 405-650 nm.

[0730] The antagonistic effect of the compounds of the present inventionon the fibrinogen receptor α_(IIb)β₃, in particular for determiningselectivity, can be ascertained as described in U.S. Pat. No. 5,403,836,p. 237.

1. A compound of the formula I, A-B-D-E-F-G (I) in which: A is

is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system, which can contain from 1 to 4 heteroatoms fromthe group N, O and S and can optionally be substituted, once or morethan once, by R¹², R¹³, R¹⁴ and R¹⁵; B is a direct linkage,(C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene, (C₃-C₈)-cycloalkylene, —C≡C—,—NR²—, —NR²C(O)—, —NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —O—C(O)—, —NR²—S(O)—,—NR²—S(O)₂—, —O—, —S— or —CR²═CR³—, which can in each case besubstituted, once or twice, by (C₁-C₈)-alkyl; D is a direct linkage,(C₁-C₈)-alkanediyl, (C₅-C₁₀)-arylene, —O—, —NR²—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —NR²—C(S)—NR²—, —OC(O)—, —C(O)O—, —S(O)—, —S(O)₂—,—S(O)₂—NR²—, —S(O)—NR²—, —NR²—S(O)—, —NR²—S(O)₂—, —S—, —CR²═CR³— or—C≡C— which can in each case be substituted, once or twice, by(C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl, with it not being possible forD to be —CO—NR²—, —C(O)O—, —S(O)—, —S(O)₂—, —S(O)—NR²— or —S(O)₂—NR²—when B is a direct linkage; E is a template which is selected from theseries of fibrinogen receptor antagonists; F is defined like D, G is

R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl, which isoptionally substituted, once or more than once, by fluorine,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ orR⁸C(O)R⁹; R⁴, R⁵, R⁶ and R⁷ are, independently of each other, H,fluorine, OH, (C₁-C₈)-alkyl, (C₃-C₁₄)-cycloalkyl,(C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, or R⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, ROC(O)R⁹,R⁸—, C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹, R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹,R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹, R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹,R⁸N(R²)S(O)N(R²)R⁹, R⁸S(O)_(n)R⁹, R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹,R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹; R⁸ is H, (C₁-C₈)-alkyl,(C₃-C₁₄)-cycloalkyl, (C₃-C₁₄)-cycloalkyl-(C₁-C₈)-alkyl, (C₅-C₁₄)-aryl or(C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, where the alkyl radicals can besubstituted, once or more than once, by fluorine; R⁹ is a direct linkageor (C₁-C₈)-alkanediyl; R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)R¹¹, P(O)(R¹¹)_(n)or a four-membered to eight-membered, saturated or unsaturatedheterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, Oand S, such as tetrazolyl, imidazolyl, pyrazolyl, oxazolyl orthiadiazolyl; R¹¹ is OH, (C₁-C₈)-alkoxy, (C₅-C₁₄)-aryl-(C₁-C₈)-alkoxy,(C₅ C₁₄)-aryloxy, (C₁-C₈)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono- ordi-((C₁-C₈)-alkyl)-amino, (C₅-C₁₄)-aryl-(C₁-C₈)-alkylamino,(C₁-C₈)-dialkylaminocarbonylmethyloxy(C₅-C₁₄)-aryl-(C₁-C₈)-dialkylaminocarbonylmethyloxy or(C₅-C₁₄)-arylamino or the radical of an L-amino acid or D-amino acid;R¹², R¹³, R¹⁴ and R¹⁵ are, independently of each other, H,(C₁-C₁₀)-alkyl which is optionally substituted, once or more than once,by fluorine, (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,(C₅-C₁₄)-aryl, (C₅-C₁₄)-aryl-(C₁-C₈)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹,R⁸OC(O)R⁹, R⁸R⁸NR⁹, R⁸—(C₅-C₁₄)-aryl-R⁹, HO(C₁-C₈)-alkyl-N(R²)R⁹,R⁸N(R²)C(O)R⁹, R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²)—NR², R²R³NC(═NR²),═O, or ═S; where two adjacent substituents from R¹² to R¹⁵ can alsotogether be —OCH₂O— or —OCH₂CH₂O—; Y is NR², O or S; n is 1 or 2; p andq are, independently of each other, 0 or 1; in all their stereoisomericforms and mixtures thereof in all proportions, and their physiologicallytolerated salts, with compounds being excepted in which E a) is a6-membered aromatic ring system which can contain up to 4 N atoms andwhich can be substituted by from 1 to 4 identical or different arbitrarysubstituents, or b) is4-methyl-3-oxo-2,3,4,5-tetrahydro-1-H-1,4-benzodiazepine.
 2. A compoundof the formula I as claimed in claim 1, in which: A is the radical

is a 5-membered to 10-membered monocyclic or polycyclic, aromatic ornonaromatic ring system which can contain from 1 to 4 heteroatoms fromthe group consisting of N, O and S and which can optionally besubstituted, once or more than once, by R¹², R¹³, R¹⁴ and R¹⁵; B is adirect linkage, (C₁-C₆)-alkanediyl, (C₅-C₈)-arylene,(C₃-C₈)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—C(O)—NR²—,—NR²—S(O)—, —NR²—S(O)₂—, —O— or —CR²═CR³— which can in each case besubstituted, once or twice, by (C₁-C₆)-alkyl; D is a direct linkage,(C₁-C₈)-alkanediyl, (C₅-C₈)-arylene, —O—, —NR²—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR²—, —OC(O)— —C(O)O—, —S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)₂—, —S—,—CR²═CR³— or —C≡C— which can in each case be substituted, once or twice,by (C₁-C₈)-alkyl, —CR²═CR³— or (C₅-C₆)-aryl, with it not being possiblefor D to be —CO—NR²—, —C(O)O—, —SO₂— or —S(O)₂—NR²— when B is a directlinkage; F is defined like D; G is

R² and R³ are, independently of each other, H, (C₁-C₁₀)-alkyl, which isoptionally substituted, once or more than once, by fluorine,(C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, R⁸C(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹; R⁴, R⁵,R⁶ and R⁷ are, independently of each other, H, fluorine, OH,(C₁-C₈)-alkyl, (C₅-C₁₄)cycloalkyl, (C₅-C₁₄)cycloalkyl-(C₁-C₈)-alkyl, orR⁸OR⁹, R⁸SR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸-(C₅-C₁₄)-aryl-R⁹, R⁸N(R²)R⁹,R⁸R⁸NR⁹, R⁸N(R²)C(O)OR⁹, R⁸S(O)_(n)N(R²)R⁹, R⁸OC(O)N(R²)R⁹,R⁸C(O)N(R²)R⁹, R⁸N(R²)C(O)N(R²)R⁹, R⁸N(R²)S(O)_(n)N(R²)R⁹, R⁸S(O)_(n)R⁹,R⁸SC(O)N(R²)R⁹, R⁸C(O)R⁹, R⁸N(R²)C(O)R⁹ or R⁸N(R²)S(O)_(n)R⁹; R⁸ is H,(C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl, (C₅-C₁₄)cycloalkyl-(C₁-C₆)-alkyl,(C₅C₁₂)-aryl or (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, where the alkyl radicalscan be substituted, once or more than once, by fluorine; R⁹ is a directlinkage or (C₁-C₆)-alkanediyl; R¹⁰ is C(O)R¹¹, C(S)R¹¹, S(O)_(n)R¹¹,P(O)(R¹¹)_(n) or a four-membered to eight-membered, saturated orunsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from thegroup N, O and S; R¹¹ is OH, (C₁-C₆)-alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkoxy, (C₅-C₁₂)-aryloxy,(C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkylcarbonyloxy-(C₁-C₆)-alkoxy, NH₂, mono-, ordi(C₁-C₆)-alkyl)-amino, (C₅-C₁₂)-aryl-(C₁-C₆)-alkylamino,(C₁-C₆)-dialkylaminocarbonylmethyloxy; R¹², R¹³, R¹⁴ and R¹⁵ are,independently of each other, H, (C₁-C₈)-alkyl which is optionallysubstituted, once or more than once, by fluorine, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, H₂N, R⁸ONR⁹, R⁸OR⁹, R⁸OC(O)R⁹,R⁸-(C₅-C₁₂)-aryl-R⁹, R⁸R⁸NR⁹, HO—(C₁-C₈)-alkyl-N(R²)R⁹, R⁸N(R²)C(O)R⁹,R⁸C(O)N(R²)R⁹, R⁸C(O)R⁹, R²R³N—C(═NR²), R²R³N—C(═NR²)—NR², ═O or ═S;where two adjacent substituents from R¹² to R¹⁵ can also together be—OCH₂O—, —OCH₂CH₂O— or —OC(CH₃)₂O—; Y is NR², or S; n is 1 or 2; p and qare, independently of each other, 0 or 1; and E is as defined in claim1; in all their stereoisomeric forms and mixtures thereof in allproportions, and their physiologically tolerated salts.
 3. A compound ofthe formula I as claimed in claim 1 and/or 2, in which: A is one of theradicals

B is a direct linkage, (C₁-C₆)-alkanediyl, (C₅-C₆)-arylene,(C₅-C₆)-cycloalkylene, —C≡C—, —NR²—, —NR²—C(O)—, —NR²—S(O)₂—, —O— or—CR²═CR³—, which can in each case be substituted, once or twice, by(C₁-C₆)-alkyl; D is a direct linkage, (C₁-C₆)-alkanediyl,(C₅-C₆)-arylene, —O—, —NR²—, —NR²—C(O)—, —C(O)NR²—, —NR²—C(O)—NR²—,—OC(O)—, —S(O)₂—NR²—, —NR²—S(O)₂— or —CR²═CR³— which can in each case besubstituted, once or twice, by (C₁C₆)-alkyl, with it not being possiblefor D to be —C(O)NR²— or —S(O)₂—NR²— when B is a direct linkage; E a) is

 where R^(1a), R^(2a)R^(20a) R^(21a) an R^(22a) are: R^(1a) and R^(2a)are, independently of each other, from one to three groups from theseries consisting of hydrogen, halogen, cyano, carboxamido,carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido,hydroxyl, mercapto or sulfonamido, or an optionally substituted radicalfrom the group consisting of C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl,C₃-C₁₂-alkynyl, C₃-C₁₂-cycloalkyl, C₆-C₁₄-aryl, C₆-C₁₀-aryl-C₁-C₈-alkyl,C₁-C₁₂-alkyloxy, C₆-C₁₄-aryloxy and C₁-C₁₂-acylamino, where thesubstituents are a radical from the group consisting of halogen, cyano,azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido,carboxamido, carbamoyloxy, formyloxy, formyl, C₁-C₄-alkoxy, phenyl andphenoxy; R^(20a) is hydrogen, halogen (fluorine, chlorine, bromine oriodine), C₁-C₄-alkoxy, C₁-C₄-alkyl, phenyl, benzyl orhalogen-C₁-C₄-alkyl, R^(21a) and R^(22a) are, independently of eachother,
 1. hydrogen
 2. (C₁-C₁₂)-alkyl
 3. (C₆-C₁₄)-aryl, 4.(C₃-C₁₄)-cycloalkyl,
 5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl, 6.(C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals defined under 2.to
 6. can be substituted by one or more radicals from the groupconsisting of halogen (fluorine, chlorine, bromine or iodine); nitro;hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where R^(24a) is a radical from the groupconsisting of C₁-C₈-alkoxy; C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy;di-C₁-C₈-alkylamino-C₁-C₈-alkoxy; acylamino-C₁-C₈-alkoxy;acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy;pivaloylethoxy; or C₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group can beoptionally substituted by from one to three radicals selected from thegroup consisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy; R²⁵ and R²⁶ are,independently of each other, hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl,C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or R²⁵ and R²⁶ together form atrimethylene, tetramethylene, pentamethylene or 3-oxopentamethyleneradical;
 7. Q²-L³ ₁ where Q² is hydrogen or Q¹; and L³ is a chemicalbond, L¹ or L²; Q¹ is a substituted or unsubstituted, positivelycharged, nitrogen-containing radical, L¹ is a divalent radical whichcontains from 3 to 9 methylene groups, where from one to all themethylene groups can be replaced with one or more alkene groups, alkynegroups, aryl groups or functional groups containing heteroatoms from thegroup consisting of N, O or S, and L² is an optionally substituted,divalent radical; and R^(22b) is:
 1. hydrogen
 2. (C₁-C₁₂)-alkyl 3.(C₆-C₁₄)-aryl,
 4. (C₃-C₁₄)-cycloalkyl,
 5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)-cycloalkyl, where the radicals defined under2. to
 6. can be substituted by one or more radicals from the groupconsisting of halogen (fluorine, chlorine, bromine or iodine); nitro;hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide;phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl; benzyl; C₃-C₁₄-cycloalkyl;COR^(24a) or CONR²⁵R²⁶; where R^(24a) is a radical from the groupconsisting of C₁-C₈-alkoxy; C₃-C₁₂-alkenoxy; C₆-C₁₂-aryloxy;di-C₁-C₈-alkylamino-C₁-C₈-alkoxy; acylamino-C₁-C₈-alkoxy;acetylaminoethoxy; nicotinoylaminoethoxy; succinamidoethoxy;pivaloylethoxy; or C₆-C₁₂-aryl-C₁-C₈-alkoxy, where the aryl group canoptionally be substituted by from one to three radicals selected fromthe group consisting of nitro, halogen, C₁-C₄-alkoxy, amino, hydroxyl,hydroxy-C₂-C₈-alkoxy or dihydroxy-C₃-C₈-alkoxy; R²⁵ and R²⁶ are,independently of each other, hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl,C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or R²⁵ and R²⁶ together form atrimethylene, tetramethylene, pentamethylene or 3-oxopentamethyleneradical;
 7. Q²-L³, where Q² is hydrogen or Q¹; and L³ is a chemicalbond, L¹ or L²; Q¹ is a substituted or unsubstituted, positivelycharged, nitrogen-containing radical, L¹ is a divalent radical whichcontains from 3 to 9 methylene groups, where from one to all themethylene groups can be replaced with one or more alkene radicals,alkyne radicals, aryl radicals or functional groups containingheteroatoms from the group consisting of N, O or S, and L² is anoptionally substituted, divalent radical; or b) is

where R^(1b) and R^(2b) are: R^(1b) and R^(2b) are, independently ofeach other, from one to three groups from the series consisting ofhydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl,azido, nitro, ureido, thioureido, hydroxyl, mercapto or sulfonamido, oran optionally substituted radical from the group consisting ofC₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, C₃-C₁₂-alkynyl, C₃-C₁₂-Cycloalkyl,C₆-C₁₄-aryl-C₆-C₁₀-aryl-C₁-C₈-alkyl, C₁-C₁₂-alkyloxy, C₆-C₁₄-aryloxy andC₁-C₁₂-acylamino, where the substituents are a radical from the groupconsisting of halogen, cyano, azido, nitro, hydroxyl, mercapto,sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy,formyl, C₁-C₄-alkoxy, phenyl and phenoxy; and R^(25b) and R^(26b) are,independently of each other, hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl,C₆-C₁₄-aryl or C₁-C₆-alkyl-C₆-C₁₀-aryl, or R^(25b) and R^(26b) togetherform a trimethylene, tetramethylene, pentamethylene or3-oxopentamethylene radical; or c) is

where (R₂)_(p) is bonded to one or more carbon atoms of the 6-memberedring and is, independently of each other, a radical from the groupconsisting of H, alkyl, halogen-substituted alkyl, hydroxyalkyl,alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxyl, alkoxy,aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen,nitro and sulfo; R is (C₁-C₄)-alkyl p is an integer from 1 to 3, or d)is

where R³ is hydrogen, (C₁-C₆)-alkyl or aryl-C₁-C₆-alkyl, or e) is

 in which V is CR^(7a) or N, and D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂or

 in which x is CR^(3a) or N  where R^(3a) is CN, C(O)N(R^(7a))R^(8a),

 in which V is CR^(7a) or N, and D^(a) is CH₂, CH₂—CH₂, CH₂C(R^(7a))₂CH₂or

 in which X is CR or N, in which R^(3a) is CN, C(O)N(R^(7a))R^(8a),

 where Y³ is O, or H₂, and R^(7a) is hydrogen; C₁-C₄-alkyl which isoptionally substituted by OH or (C₁-C₄)-alkoxy; C₂-C₆-alkenyl which isoptionally substituted by (C₁-C₄)-alkoxy; or OH(C₁-C₄)-alkylaryl; oraryl which is optionally substituted by identical or different radicalsfrom the group consisting of halogen, (C₁-C₄)-alkoxy, hydroxyl or(C₁-C₄)-alkyl, R^(8a) is hydrogen or C₁-C₄-alkyl, n is an integer from 0to 7, and n′ is an integer from 0 to 3; or f) is

where: X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)-group,where R^(2b) is a hydrogen atom, a straight-chain or branched alkylgroup having from 1 to 15 carbon atoms, a straight-chain or branchedalkenyl or alkynyl group having in each case from 3 to 10 carbon atoms,where the double bond or triple bond cannot connect directly to thenitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each casefrom 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, analkyl group having from 2 to 6 carbon atoms which is substituted, fromthe 1 position to the nitrogen atom of the —NR^(2b) group onwards, by anR^(3b)O, (R^(3b))₂N—, R^(4b)CO—NR^(3b)—, alkylsulfonyl-NR^(3b)—,arylsulfonyl-NR^(3b)—, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group having from 1 to 6 carbon atoms which issubstituted by one or two aryl groups, R^(6b)OCO; (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—CO-alkylene-NR³—CO—, (R^(3b))₂N—CO-alkylene-NR^(3b)or R^(5b)CO-alkylene-NR^(3b)—CO— group, in which R^(3b) and R^(5b) aredefined as indicated below and R^(6b) is a hydrogen atom, an alkyl grouphaving from 1 to 6 carbon atoms, a cycloalkyl group having from 5 to 7carbon atoms or an aralkyl group, Y′ is an NO-group, a nitrogen atom ora methine group which is optionally substituted by an alkyl group, Z₁,Z₂, Z₃ and Z₄, which can be identical or different, are methine groups,carbon atoms, imino groups or nitrogen atoms, where at least one of theradicals Z₁ to Z₄ has to contain a carbon atom, and one or two methinegroups which are adjacent to a nitrogen atom can in each case bereplaced by carbonyl groups, Z₅ and Z₆ are in each case a carbon atom,or else one of the radicals Z₅ or Z is a nitrogen atom and the other ofthe radicals Z₅ or Z₆ is a carbon atom, R^(3b) is a hydrogen atom, analkyl group having from 1 to 6 carbon atoms, or an aryl, aralkyl,carboxyalkyl or alkoxycarbonylalkyl group, R^(4b) is a hydrogen atom, analkyl or alkoxy group having in each case from 1 to 6 carbon atoms, oran aryl or aralkyl group having from 1 to 6 carbon atoms in the alkylmoiety, and R^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an imino group which issubstituted by an R₃, R₄CO—, alkylsulfonyl or arylsulfonyl group, whereR₃ and R₄ are defined as mentioned above; F is a direct linkage,(C₁-C₆), alkanediyl, —O—, O—NR²—, —NR²—CO—, —NR²—C(O)—NR²—, —OC(O)—,—C(O)O—, —CO—, —S(O)₂—, —S(O)₂—NR²—, —NR²—S(O)₂—, —CR²═CR³—, —C≡C— whichcan in each case be substituted, once or twice, by (C₁-C₆)-alkyl; G is

R² and R³ are, independently of each other, H, (C₁-C₆)-alkyl which isoptionally substituted, once or more than once, by fluorine,(C₅-C₆)Cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, R⁸OC(O)R⁹, R⁸R⁸NC(O)R⁹ or R⁸C(O)R⁹; R⁴, R⁵,R⁶ and R⁷ are, independently of each other, H, fluorine, OH,(C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl, (C₅-C₁₄)-cycloalkyl-(C₁-C₆)-alkyl,or R⁸OR⁹, R⁸CO₂R⁹, R⁸OC(O)R⁹, R⁸—(C₅-C₁₀)-aryl-R⁹, R⁸NHR⁹, R⁸R⁸NR⁹,R⁸NHC(O)OR⁹, R⁸S(O)_(n)NHR⁹, R⁸OC(O)NHR⁹, R⁸C(O)NHR⁹, R⁸C(O)R⁹,R⁸NHC(O)NHR⁹, R⁸NHS(O)_(n)NHR⁹, R⁸NHC(O)R⁹ or R⁸NHS(O)_(n)R⁹, where atleast one radical from the group R⁴, R⁵, R⁸ and R⁷ is a lipophilicradical; R⁸ is H, (C₁-C₆)-alkyl, (C₅-C₁₄)-cycloalkyl,(C₅-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl or(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, where the alkyl radicals can be substitutedby from 1 to 6 fluorine atoms; R⁹ is a direct linkage or(C₁-C₆)-alkanediyl; R¹⁰ is C(O)R¹¹; R¹¹ is OH, (C₁-C₆)-alkoxy,(C₅-C₁₀)-aryl-(C₁-C₆)-alkoxy, (C₅-C₁₀)-aryloxy,(C₁-C₆)-alkylcarbonyloxy-(C₁-C₄)-alkoxy,(C₅-C₁₀)-aryl-(C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi(C₁-C₆)-alkyl)-amino; R¹² is H, (C₁-C₆)-alkyl which is optionallysubstituted, once or more than once, by fluorine, (C₃-C₆)-cycloalkyl,(C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl, (C₅-C₁₀)-aryl,(C₅-C₁₀)-aryl-(C₁-C₄)-alkyl, H₂N, R⁸OR⁹, R⁸OC(O)R⁹, R⁸-(C₅-C₁₀)-aryl-R⁹,R⁸R⁸NR⁹, R⁸NHC(O)R⁹, R⁸C(O)NHR⁹, H₂N—C(═NH)—, H₂N—C(═NH)—NH— or ═O;where two adjacent substituents R¹² can together also be —OCH₂O— or—OCH₂CH₂O—; Y is NR², O or S; n is 1 or 2; and p and q are,independently of each other, 0 or 1; in all their stereoisomeric formsand mixtures thereof in all proportions, and their physiologicallytolerated salts.
 4. A compound of the formula I as claimed in one ormore of claims 1 to 3, in which: A is one of the radicals

B is a direct linkage, (C₁-C₄)-alkanediyl, phenylene, pyridindiyl,thiophenediyl, furandiyl, cyclohexylene, cyclopentylene, —C═C— orCR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₄)-alkyl; D is a direct linkage, (C₁-C₄)-alkanediyl or phenylene,—O, —NR²—, —NR²—C(O)—, —C(O)—NR², —NR²—S(O)₂, —NR²—C(O)—NR²— or—CR²═CR³— which can in each case be substituted, once or twice, by(C₁-C₄)-alkyl, with it not being possible for D to be —C(O)—NR²— when Bis a direct linkage; E a) is

 where R^(1a), R^(20a), R^(21a), R^(22a) and R^(22b) are in this case:R^(1a) is, independently of each other, from one to three groups fromthe series consisting of hydrogen and halogen (fluorine, chlorine,bromine or iodine); R^(20a) is hydrogen; R^(21a) and R^(22a) are,independently of each other,
 1. hydrogen,
 2. (C₁-C₆)-alkyl, 3.(C₆-C₁₂)-aryl,
 4. (C₆-C₁₂)-cycloalkyl,
 5. (C₁-C₆)-alkyl-(C₆-C₁₂)-aryl,6. (C₁-C₆)-alkyl-(C₆-C₁₂)-cycloalkyl, where the radicals defined under2. to
 6. can be substituted by one or more radicals from the groupconsisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide,(C₁-C₆)-alkyl, (C₆-C₁₂)-aryl, benzyl or (C₆-C₁₂)-cycloalkyl; R^(22b) is1 hydrogen,
 2. (C₁-C₁₂)-alkyl,
 3. (C₆-C₁₄)-aryl,
 4. (C₃-C₁₄)-cycloalkyl,5. (C₁-C₁₂)-alkyl-(C₆-C₁₄)-aryl,
 6. (C₁-C₁₂)-alkyl-(C₃-C₁₄)cycloalkyl,where the radicals defined under
 2. to
 6. can be substituted by one ormore radicals from the group consisting of halogen (fluorine, chlorine,bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate;sulfonamide; trifluoroimide; phosphonate; C₁-C₆-alkyl; C₆-C₁₄-aryl;benzyl; C₃-C₁₄-cycloalkyl; COR^(24a) or CONR²⁵R²⁶; where R^(24a) is aradical from the group consisting of C₁-C₈-alkoxy; C₃-C₁₂-alkenoxy;C₆-C₁₂-aryloxy; di-C₁-C₈-alkylamino-C₁-C₈-alkoxy;acylamino-C₁-C₈-alkoxy; acetylaminoethoxy; nicotinoylaminoethoxy;succinamidoethoxy; pivaloylethoxy; or C₆-C₁₂-aryl-C₁-C₈-alkoxy, wherethe aryl group can be optionally substituted by from one to threeradicals selected from the group consisting of nitro, halogen,C₁-C₄-alkoxy, amino, hydroxyl, hydroxy-C₂-C₈-alkoxy anddihydroxy-C₃-C₈-alkoxy; R²⁵ and R²⁶ are, independently of each other,hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl orC₁-C₆-alkyl-C₆-C₁₀-aryl, or R²⁵ and R²⁶ together form-a trimethylene,tetramethylene, pentamethylene or 3-oxopentamethylene radical;
 7. Q²-L³where Q² is hydrogen or Q¹; and L³ is a chemical bond or L¹; Q¹ is anamino, amidino, aminoalkylenimino, iminoalkylenamino or guanidino group,preferably an amidino group; L¹ is C₆-C₁₄-aryl-C₂-C₄-alkynylene;C₆-C₁₄-aryl-C₁-C₃-alkylene; C₆-C₁₄-aryl-C₁-C₃-alkyloxyene or—R^(14c)—CO—NR^(6c)R^(15c), where R^(6c) is hydrogen, C₁-C₄-alkoxy,C₁-C₄-alkyl or halogen-C₁-C₄-alkyl; R^(14c) is a chemical bond,C₁-C₈-alkylene, C₃-C₇-cycloalkylene, C₂-C₅-alkenylene, C₃-C₅-alkynylene,C₆-C₁₀-arylene, C₁-C₃-alkyl-C₆-C₁₂-arylene,C₁-C₂-alkyl-C₆-C₁₀-aryl-C₁-C₂-alkylene, C₆-C₁₀-aryl-C₁-C₂-alkylene orC₆-C₁₀-aryloxy-C₁-C₂-alkylene, and R^(15c) is a chemical bond,C₁-C₄-alkylene, C₂-C₄-alkenylene, C₂-C₄-alkynylene, C₆-C₁₀-arylene orC₁-C₃-alkyl-C₆-C₁₂-arylene; or b) is

 where R_(1b), R^(2b), R^(25b) and R^(26b) are in this case: R^(1b) andR^(2b) are, independently of each other, from one to three groups fromthe series consisting of hydrogen and halogen (fluorine, chlorine,bromine or iodine); and R^(25b) and R^(26b) are, independently of eachother, hydrogen, C₁-C₁₀-alkyl, C₃-C₁₀-alkenyl, C₆-C₁₄-aryl orC₁-C₆-alkyl-C₆-C₁₀-aryl, or R^(25b) and R^(26b) together form atrimethylene, tetramethylene, pentamethylene or 3-oxopentamethyleneradical; or c) is

or d) is

or e) is

 where Y³, V and D^(a) are defined as described above; or f) is

where: X′ is an oxygen, sulfur or nitrogen atom or an —NR^(2b)-group,where R^(2b) is a hydrogen atom, a straight-chain or branched alkylgroup having from 1 to 15 carbon atoms, a straight-chain or branchedalkenyl or alkynyl group having in each case from 3 to 10 carbon atoms,where the double bond or triple bond cannot connect directly to thenitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each casefrom 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, analkyl group having from 2 to 6 carbon atoms which is substituted, fromthe β position to the nitrogen atom of the —NR^(2b)— group onward, by anR^(3b)O—, (R^(3b))₂N—, R^(4b)CO—NR^(3b), alkylsulfonyl-NR^(3b),arylsulfonyl-NR^(3b), alkylsulfenyl, alkylsulfinyl, alkylsulfonyl orR^(5b) group, or an alkyl group, having from 1 to 6 carbon atoms whichis substituted by one or two aryl groups, R^(6b)OCO—, (R^(3b))₂NCO—,R^(5b)—CO—, R^(3b)O—CO-alkylene-NR^(3b)—CO—,(R^(3b))₂N—CO-alkylene-NR^(3b)—CO— or R^(5b)CO-alkylene-NR^(3b)—CO—group, in which R^(3b) and R^(5b) are defined as indicated below andR^(6b) is a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkylgroup, Y′ is an NO-group, a nitrogen atom or a methine group which isoptionally substituted by an alkyl group, Z₁, Z₂, Z₃ and Z₄, which canbe identical or different, are methine groups, carbon atoms, iminogroups or nitrogen atoms, where at least one of the radicals Z₁ to Z₄has to contain a carbon atom, and one or two methine groups which areadjacent to a nitrogen atom can in each case be replaced by carbonylgroups, Z₅ and Z₆ are in each case a carbon atom, or else one of theradicals Z₅ or Z₆ is a nitrogen atom and the other of the radicals Z₅ orZ₆ is a carbon atom, R^(3b) is a hydrogen atom, an alkyl group havingfrom 1 to 6 carbon atoms, or an aryl, aralkyl, carboxyalkyl oralkoxycarbonylalkyl group, R^(4b) is a hydrogen atom, an alkyl or alkoxygroup having in each case from 1 to 6 carbon atoms, or an aryl oraralkyl group having from 1 to 6 carbon atoms in the alkyl moiety, andR^(5b) is an azetidino, pyrrolidino, hexamethylenimino orheptamethylenimino group or a piperidino group in which the methylenegroup in the 4 position can be replaced by an oxygen atom, by asulfenyl, sulfinyl or sulfonyl group, or by an imino group which issubstituted by an R^(3b), R^(4b)CO—, alkylsulfonyl or arylsulfonylgroup, where R^(3b) and R^(4b) are defined as mentioned above, F is adirect linkage, (C₁-C₆)-alkanediyl, —O—, —CO—NR²—, —NR²—CO—,—NR²—C(O)—NR², —S(O)₂—NR², —NR²—S(O)₂—, —CR²═CR³—, or —C≡C— which can ineach case be substituted, once or twice, by (C₁-C₄)-alkyl;, G is

R² and R³ are, independently of each other, H, (C₁-C₄)-alkyl,trifluoromethyl, pentafluoroethyl, (C₅-C₆)-cycloalkyl,(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, phenyl or benzyl; R⁴ is(C₁₀-C₁₄)-cycloalkyl, (C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl, or R¹⁶OR⁹,R¹⁶NHR⁹, R¹⁶NHC(O)OR⁹, R¹⁶S(O)_(n)NHR⁹, R¹⁶OC(O)NHR⁹, R¹⁶C(O)NHR⁹,R¹⁶C(O)R⁹, R¹⁶NHC(O)R⁹ or R¹⁶NHS(O)_(n)R⁹; R⁵ is H, (C₁-C₆)-alkyl,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, trifluoromethyl,pentafluoroethyl, phenyl or benzyl; R⁸ is H, (C₁-C₄)-alkyl,(C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl, phenyl, benzyl,trifluoromethyl or pentafluoroethyl; R⁹ is a direct linkage or(C₁-C₄)-alkanediyl; R¹⁰ is C(O)R¹¹; R¹¹ is OH, (C₁-C₆)-alkoxy, phenoxy,benzyloxy, (C₁-C₄)-alkylcarbonyloxy-(C₁-C₄)-alkoxy, NH₂ or mono- ordi(C₁-C₆)-alkyl)amino; R¹² is H, (C₁-C₄)-alkyl, trifluoromethyl,pentafluoroethyl, (C₅-C₆)-cycloalkyl, (C₅-C₆)-cycloalkyl-(C₁-C₂)-alkyl,(C₅-C₆)-aryl, (C₅-C₆)-aryl-(C₁-C₂)-alkyl, H₂N, R⁸R⁸NR⁹, R⁸NHC(O)R⁹,H₂N—C(═NH) or H₂N—C(═NH)—NH—; where two adjacent substituents R¹² canalso be —OCH₂O— or —OCH₂CH₂O—; R¹⁶ is (C₁₀-C₁₄)-cycloalkyl or(C₁₀-C₁₄)-cycloalkyl-(C₁-C₄)-alkyl which can optionally be substituted,once or twice, by (C₁-C₄)-alkyl, trifluoromethyl, phenyl, benzyl,(C₁-C₄)-alkoxy, phenoxy, benzyloxy, ═O or mono- ordi(C₁-C₄)-alkyl)-amino, where the cycloalkyl radicals are preferably1-adamantyl or 2-adamantyl, which can be substituted as described above;n is 1 or 2; and q is 0 or 1; in all their stereoisomeric forms andmixtures thereof in all proportions, and their physiologically toleratedsalts.
 5. A compound of the formula I as claimed in one or more ofclaims 1 to 4, in which the distance between R¹⁰ and the first N atom inA is from 12 to 13 covalent bonds along the shortest route between theseatoms, in all its stereoisomeric forms and mixtures thereof in allproportions, and its physiologically tolerated salts.
 6. A process forpreparing a compound of the formula I as claimed in one or more ofclaims 1 to 5, which comprises linking, by means of fragmentcondensation, two or more fragments which can be derivedretrosynthetically from the formula I.
 7. A compound of the formula I asclaimed in one or more of claims 1 to 5, and/or its physiologicallytolerated salts, for use as a pharmaceutical.
 8. A compound of theformula I as claimed in one or more of claims 1 to 5, and/or itsphysiologically tolerated salts, for use as an inhibitor of boneresorption by osteoclasts, as an inhibitor of tumor growth or tumormetastasis, as an inflammation inhibitor, for the treatment orprophylaxis of cardiovascular diseases, for the treatment or prophylaxisof neuropathies or retinopathies, or as a vitronectin receptorantagonist for the treatment or prophylaxis of diseases which are basedon the interaction between vitronectin receptors and their ligands incell-cell or cell-matrix interaction processes.
 9. A pharmaceuticalpreparation, comprising at least one compound of the formula I asclaimed in one or more of claims 1 to 5, and/or its physiologicallytolerated salts, in addition to pharmaceutically unobjectionable carrierand auxiliary substances.